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Of Bloom syndrome (BS)cells [36]. The minimal helicase functional unit of BLM also includes an RQC domain, which specifically mediates binding to G4 DNA and other DNA structures [37]. The helicase activity, along with interactions with TOP3α and RMI1 to form the BTR complex, is essential for possibly all BLM functions (Fig. 1).The most well-studied mutant of BLM is K695A, which is completely defective in both ATPase activity and helicase unwinding activity [38]. The HRDC domain in BLM plays a role in recruiting it to specific DNA lesions [39], and this region is thought to contribute to BLM’s conformational change [40]. A nuclear localization signal (NLS) has been identified in the carboxyl-terminal region of BLM [34]. BLM functions as a single-stranded (ss) DNA translocase by interacting physically and functionally with ssDNA-binding (SSB) proteins, such as replication protein A (RPA) and RAD51 [41,42,43], thus highlighting the multifaceted genome maintenance function of BLM.The expression of BLM is regulated by the cell cycle. BLM protein accumulates at high levels during S phase, persists in G2/M, and is undetectable in G1, suggesting rapid degradation during mitosis [42, 44]. This regulation is likely tied to BLM’s function in DNA replication in the S phase and homologous recombination in the G2 phase. Notably, during S phase, BLM colocalizes with RPA at replication foci and restarts stalled replication forks [45]. Cdc5-mediated hyperphosphorylation of BLM may reduce its DNA unwinding activity during mitosis [46]. In response to DNA damage, the localization and expression regulation of BLM are altered. For example, treatment with hydroxyurea (HU) induces the relocalization of BLM to RAD51 and p53 foci at sites of stalled DNA replication forks to inhibit homologous recombination and help maintain genomic integrity [47]. Furthermore, HU treatment leads to a significant increase in BRCA1 and BLM colocalization, which appears to be specific to cells in the S and G2 phases [48].Fig. 1Schematic representation of the structural domains of BLM from Homo sapiens. Abbreviations: NLS, nuclear localization sequence; HRDC, helicase and RNase D-like C-terminal domain; RQC, RecQ C-terminal domain. The figure shows interacting proteins and their direct binding sites in the regulation of ALTFull size imageBLM’s interaction proteins and functionsThe execution of certain BLM functions relies on its interactions with other proteins. BLM forms a BTR complex and plays a key role in the resolution of intertwined DNA structures during DNA replication and DNA damage repair [49]. BLM can interact with RPA Telomere lengthening during the G2/M phase, which facilitates RAD52-dependent BIR for telomere synthesis and requires BLM for resolving BIR intermediates, recruiting RAD52 and other DDR proteins to APBs, and generating replication stress [72]. This pathway is also compensated by a RAD52-independent but BLM-dependent pathway to produce C-circles [9, 76]. Since the function of BLM in ALT pathways is complex and precisely regulated, here, we attempt to sort out the regulators of BLM in the ALT mechanism according to the latest studies (Fig 3).Fig. 3Summary of the positive and negative regulators that modulate the activity of BLM or the BTR complex in ALTFull size imageFactors that promoted BLM activity in ALTBesides the shelterin complex and PML, which can recruit BLM to APBs, recent studies have emphasized the FANCM-BTR complex as a key regulator of ALT homeostasis [17], which may have evolved to process both G4s by BLM [97] and R-loops by FANCM [32]. FANCM binds to the BTR complex via its MM2 domains, and the FANCM-BTR is essential for replication fork remodeling of ALT telomeres, thereby maintaining telomere integrity [17]. Disrupting the FANCM-BTR exacerbates DSBs and ultimately results in the loss of ALT cell viability [32]. Depletion of COUP-TFII/TR4 resulted in a significant decrease in BLM signals at telomeres, suggesting that COUP-TFII/TR4 might induce different DNA repair pathways in ALT besides the FANCM pathway [98]. BLM was also found to interact with TERRA [99], and the depletion of TERRA resulted in the reduction of BLM recruitment to ALT telomeres and telomere clustering, indicating that TERRA could serve as a scaffold to recruit BLM and other ALT-associated proteins, such as RPA, to promote APB formation [100].Factors that restrict BLM activity in ALTAlthough overexpression of BLM recapitulates important steps for ALT activation [76], BLM activity seems to contribute to the hyper-ALT phenotypes, leading to genomic toxicity and ALT cell death. Thus, many proteins have been reported to interact with BLM to limit its activity in ALT. Similar to BS, genomic instability syndrome Fanconi anemia (FA) is caused by mutations in FA proteins that participate in DNA repair processes and replication pathways [101]. Twenty-two distinct FA genes have been identified to date. In response to DNA damage, eight FA proteins (A, B, C, E, F, G, L, and M) form the FA “core” complex that recruits and monoubiquitylates two downstream FA proteins, FANCD2 and FANCI. The mono-ubiquitylation of FANCI-D2 complex then recruits and activates

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In VA13/WI38 and U2OS ALT cells by suppressing aberrant recombination within telomeres [24]. However, activation of ALT phenotypes is also observed in WRN-deficient cells, suggesting that WRN may be dispensable for ALT [25]. In contrast to WRN, BLM appears to be more closely associated with the ALT mechanism. BLM colocalizes with telomeres in ALT human cells but not in telomerase-positive immortal cell lines or primary cells [22]. Depletion of BLM leads to telomere shortening in ALT cells but does not affect telomere length in cells immortalized by telomerase [26]. Furthermore, BLM overexpression results in ALT-specific accumulation of telomeric DNA [22]. BLM functions to dissolute BIR recombination intermediates as a component of the BTR complex (composed of BLM helicase, topoisomerase TOP3α, RMI1 and RMI2) [22, 27], which is critical for triggering ALT since tethering the BTR complex to telomeres is sufficient to induce ALT phenotypes in non-ALT cells [28]. Additionally,, BLM plays additional roles in recombination to promote the ALT pathway by recruiting endonucleases such as DNA2 or EXO1 for 5’ end resection and cooperating with POLD3 in branch migration and template copying of the invading strand [29,30,31]. Although BLM is known to be critical for ALT, there are still many questions about its exact function in ALT. For instance, although BLM is required for ALT telomere maintenance and genomic stability, in certain contexts, such as FANCM-depleted, SLX4/SLX4IP-depleted and EXD2-depleted cells, BLM may cause toxicity by eliciting hyperactive ALT and associated telomere dysfunction [7, 32, 33]. Is the function of BLM in regulating ALT is associated with different genetic backgrounds? This review will discuss the BLM functions in ALT, including processing recombination intermediates during BIR or enhancing DSB end resection, and explores emerging therapeutic strategies targeting ALT-positive cancers.BLM: structure, binding partners, and function in DNA metabolismThe domains and expression of BLM helicaseThe BLM protein consists of 1,417 amino acids and shares three highly conserved protein domains with the RecQ helicase DNA subfamily: the core helicase domain (which contains an ATP binding site and an Asp-Glu-x-His (DExH) sequence), the RecQ C-terminal (RQC) domain, and the helicase and RNase D-like C-terminal (HRDC) domain (Fig. 1) [34]. The helicase activity is required for unwinding a wide variety of DNA substrates, many of which resemble DNA repair intermediates, such as DNA G4s, R-loops, D-loops, Holliday junctions (HJs) and stalled replication forks [35]. This activity also indicates that BLM functions in correcting the genomic instability characteristic. Blm Wallpaper. Blm Signs. Blm Quotes. Luxury Backless Evening Dress With Corset Back. Formal Embellished Fitted Outerwear. Yellow Beaded Drop Earrings For Festival. BLACK LIVES MATTER. blacklifematters socialjustices history civilrights protest signs poster blm quotes blm wallpaper blm art blm signs speakup faith mlk important See a recent post on Tumblr from @wallpapersbykay about blm wallpaper. Discover more posts about blm wallpaper.

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Repair pathways. BLM is thought to primarily affect DSB repair. DSBs are critical DNA damage events that cause mutations and genome instability, eventually leading to cell death or tumorigenesis. In mammalian cells, DSBs are repaired mainly by non-homologous end-joining (NHEJ, also known as c-NHEJ), alternative non-homologous end joining (a-NHEJ) and homologous recombination (HR). Emerging evidence supports a role for BLM in HR. BLM physically interacts with HR proteins, such as RAD51 and BRCA1 [47, 48]. DSB end resection is one of the earliest steps of recombinational DNA repair, and is mediated by 3’-5’ helicase and 5’-3’ nuclease activity. BLM is an essential component of both the DNA2-dependent and EXO1-dependent pathways for long-range resection [29]. BLM can also selectively bind Holliday junctions and promote ATP-dependent branch migration [61]. However, in some cases, BLM shows anti-recombination activity. It can disrupt the RAD51-ssDNA nucleoprotein filament by dislodging the human RAD51 protein from ssDNA, which disrupts the D-loop formation and HR initiation [62]. In cells lacking BRCA1 or BRCA2, ablation of BLM rescues genomic integrity and defective HR by allowing the accumulation of RAD51 at resected DSBs, resulting in cell survival in the presence of DNA damage [63]. Therefore, BLM displays both pro-and anti-recombinogenic activities, each of which contributes to the maintenance of genomic integrity.Telomere maintenanceBLM mutant cells are characterized by an excess of various chromatid lesions, including hyper-recombination and telomere associations, which is defined as a phenotype in cells with defective telomere maintenance [41], suggesting a role for BLM in telomere maintenance. Telomeres are especially susceptible to replication stress because of the enrichment of secondary structures such as G-quadruplexes, D-loops, and T-loops [64]. It is essential to remove G-quadruplexes and unwind T-loops to prevent fork stalling and telomere loss during replication, which may partly explain the importance of RecQ helicases in telomere replication. In addition, BLM interacts with shelterin proteins, such as TRF1, TRF2 and POT1 to regulate the unwinding of telomeric D-loops, suggesting a function for BLM in cells that employ recombination-mediated telomeric DNA synthesis [22, 65, 66]. Telomeres and chromosomal fragile sites (CFSs) are specific loci that are prone to breakage, probably due to their difficult-to-replicate characteristics. BLM helicase cooperates with the MUS81-EME1 resolvase complex to prevent uncontrolled chromosome breakage in CFSs in normal cells [67]. In BLM-deficient cells, G4 accumulation is observed, causing telomere fragility [68], which indicates a function of BLM in resolving telomere and whole genome replication problems. However, in some studies, primary cells derived from BS patients demonstrate comparable telomere length to age-matched controls, indicating that BLM may not be a major regulatory factor in maintaining telomere length [41]. Rather than unwinding G4 or preventing telomere fragility, BLM exhibits more complicated functions in ALT cells, either by promoting the correct replication of telomeres or dissociating HR intermediates. The detailed mechanism of BLM in ALT will be further discussed below.The role of BLM in ALT activationOwing to the dysregulated telomeric chromatin status, the interspersion of telomere variant repeats, the elevated levels of TERRA (Telomeric repeat-containing RNA), and abundant telomeric R-loops, the replication of ALT telomeres is more stressful, resulting in the accumulation of higher levels of telomeric DNA damage [69,70,71]. It has been proposed that elevated telomeric replication stress promotes break-induced telomere synthesis at ALT telomeres. The balance between extensive DNA damage and homology-directed repair is precisely regulated to activate or maintain ALT mechanisms, and BLM is one of the known drivers of ALT. In terms of regulating replication stress, BLM’s helicase activity is required to reduce replication stress and promote ALT-associated phenotypes by unwinding G-quadruplexes and duplex DNA [22]. Loss of FANCM, a DNA translocase that interacts with the BTR complex and suppresses telomeric R-loops, increases replication stress at telomeres and enhances ALT features [32]. BLM is likely to contribute to end resection in FANCM-depleted ALT cells, which leads to hyper-activation of ALT and toxicity in cells [32]. However, the helicase activity of BLM has also been shown to be required for the generation of replication stress and BIR at ALT telomere [72]. On the other hand, BLM might promote homology-directed repair by both enhancing end resection or processing recombination intermediates. In a most recent report, BLM is also shown to be responsible for assembling the ALT telomere DNA damage response through its helicase-dependent genesis of 5’-ssDNA flaps on lagging strand telomeres, suggesting that the helicase activity of BLM at lagging strand telomeres would be the initiating event of ALT [73].BLM drives ALT by promoting APB formationEmerging evidence shows that telomere clustering and BLM are required for the onset of the ALT pathway. APBs are unique nuclear structures that are present specifically in ALT cells, and are considered as a “recombinogenic microenvironment” and bring clustering telomeres and DNA repair proteins to promote ALT [74]. BLM and TRF2 or POT1 colocalize in APBs and stimulate BLM to unwind

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Telomeric forked duplexes and D-loop structures, thereby promoting recombination-driven amplification of telomeres in ALT cells [22, 26, 65, 66]. However, the interaction between BLM and TRF1 inhibits BLM unwinding of telomeric substrates, possibly because TRF1 and TRF2 function to coordinate BLM activity in cells using ALT [66]. (Fig. 2, A). Intriguingly, the N-terminus of BLM was shown to be required for its telomere binding during the S/G2 phase [75], and the colocalization of BLM with TRF2 and PML reached a maximum during the late S, G2 and M phases, which is consistent with the reported enrichment of APBs during G2/M when ALT is initiated [66]. Depletion of BLM with siRNAs drastically abolishes APB and ALT telomere synthesis in G2 [9, 15], whereas overexpression of the BLM helicase not only results in the localization at APBs in the presence of telomere clustering induced by engineering poly(SUMO)/poly(SIM) scaffolds but also triggers hallmarks of the ALT pathway in ALT cells [76]. By tethering PML-IV (a splicing variant of PML, which is the only PML variant that restors telomere clustering and telomere synthesis in PML knockout cells) to telomeres, BLM was observed to induce replication stress in APBs, which is essential for ALT telomere synthesis [72].Moreover, the SUMO-SIM interactions of telomeres with BLM, RAD52 and RAD51AP1 can induce the formation of nuclear structures with features of liquid‒liquid phase separation (LLPS) and reminiscent APBs formation in a PML-independent manner [77](Fig. 2, A).BLM is required for maintaining telomere structure and length in ALT cellsBLM drives ALT not only by promoting APB formation and telomere clustering but also by processing BIR intermediates and facilitating mitotic DNA synthesis (MiDAS). BIR is known as homology-directed DNA synthesis, which has been proceeded by strand invasion followed by the migration of a D‐loop intermediate [78, 79]. The D‐loop intermediates can be processed either by resolution (catalyzed by structure‐specific endonucleases) or by dissolution (catalyzed by the RecQ helicase) [80, 81]. Disruption of BLM causes telomere length attrition only in cells using ALT, which is likely due to the helicase activity of BLM functioning at the stalled replication forks within the ALT telomere DNA [26]. In cells harboring PML-IV-induced APBs, loss of BLM helicase activity leads to a dramatic increase in telomeric anaphase bridges in mitotic cells, suggesting that BLM promotes ALT telomere extension by resolving BIR intermediates via its helicase activity [72]. In addition to its helicase activity, the BTR complex is

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Other DNA damage response proteins, which remove interstrand crosslinking (ICL) sites and induce HR to repair DNA damage [101]. Several FA proteins are directly associated with ALT telomere replication. For instance, FANCD2 localizes to APBs, and depletion of FANCD2 leads to hyperactivation of ALT-associated phenotypes, including increases in telomere length, APB size, ECTR number, telomere dysfunction induced foci (TIFs) and fragile telomeres in ALT cells. Moreover, the co-depletion of BLM suppresses these hyper-ALT phenotypes. Mechanically, the monoubiquitylation of FANCD2 plays an antagonistic role in restraining BLM from over-resection of stalled forks in ALT cells, thus inhibiting telomere replication and recombination [18]. In addition, depletion of FANCD2 increases the signals of BLM at telomeres [98], indicating FANCD2 is a negative regulator of the BLM-dependent telomeric DNA synthesis pathway in ALT cells.FANCM also restricts uncontrolled BLM [32]. Mammalian FANCM homologs mediate branch migration, replication fork reversal and 3’-5’ DNA helicase activity [102]. In ALT cells, depletion of FANCM induces robust telomere replication stress and damage, elevated APBs and ECTRs, and the accumulation of BLM and BRCA1 at ALT telomeres [32, 103]. In addition, FANCM directly displaces BLM from telomeres. Although both FANCD2 and FANCM have been shown to suppress BLM toxicity in ALT cells, this is unlikely due to the general role of the FA pathway since the expression of the FANCM MM1 domain mutant in ALT cells is unable to recruit the FA complex to chromatin and suppress all ALT-associated features [17].SLX4IP (SLX4 interacting factor) and SLX4 counter BLM-mediated telomere clustering to coordinate the resolution and dissolution of recombination intermediates in the ALT mechanism [7, 31]. The telomere replication intermediates, such as D-loops and HJs are substrates for both the SLX4-nuclease complex and the BLM helicase. The helicase activity of BLM is able to suppress the nuclease activity of SLX4 in processing telomeric D-loops and HJs in vitro [104]. It was demonstrated that the ALT-mediated telomere synthesis, which is followed by BTR complex-modulated telomeric dissolution is counteracted by the SLX4-SLX1-ERCC4 complex, which prematurely resolves the recombination intermediate after telomere strand invasion [31]. SLX4IP binds to both BLM and SLX4 and counterbalances the dissolution activity of BLM to ensure the appropriate processing of ALT telomeres and prevent telomere breakage [7].Mismatch repair (MMR) is initiated by heterodimers MSH2/MSH6 (MutSα) or MSH2/MSH3 (MutSβ), where MSH3 and MSH6 compete for binding to MSH2 [105]. The MutSα complex is proved to interact with the BLM helicase. Blm Wallpaper. Blm Signs. Blm Quotes. Luxury Backless Evening Dress With Corset Back. Formal Embellished Fitted Outerwear. Yellow Beaded Drop Earrings For Festival. BLACK LIVES MATTER. blacklifematters socialjustices history civilrights protest signs poster blm quotes blm wallpaper blm art blm signs speakup faith mlk important See a recent post on Tumblr from @wallpapersbykay about blm wallpaper. Discover more posts about blm wallpaper.

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To unwind DNA duplexes during replication, recombination, or repair [50]. In addition, BLM has been shown to interact with proteins critical for proper DSB repair, such as BRCA1, MLH1, FANCJ/M, EXO1, FEN1 and the MRN complex (MRE11-RAD50-NBS1); the topoisomerases TOP1 and TOP2α; the DNA damage response proteins p53, 53BP1, and H2AX; the telomere-binding proteins TRF1, TFR2, and POT1; the helicase-like proteins PICH, polymerase Polη and Polδ; and others [51, 52].DNA replicationBLM helicase is involved in several replication-associated events of DNA replication, including Okazaki fragment processing, DNA strand elongation, and the resolution of replicative stress. BLM interacts with FEN1, a 5’-flap endonuclease/5’-3’ exonuclease, indicating its role in Okazaki fragment maturation [53]. BLM also participates in extension of the leading strand by interacting with p12, the smallest subunit of human Polδ, suggesting that BLM might be recruited to replication sites [54]. The physical interaction between BLM and 53BP1 leads to Chk1-mediated S-phase arrest, suggesting a potential role of BLM in the DNA replication checkpoint [55]. The helicase activity of BLM is thought to play important roles in replication fork restart. Replicative stress can be induced by various factors, including protein‒DNA complexes, RNA: DNA hybrids and accumulated atypical DNA structures such as quadruplexes, hairpins or HJs. BLM is essential for stabilizing stalled replication forks and promoting fork progression, mainly due to its ability to unwind unusual DNA secondary structures and prevent hyperrecombination [49, 56]. Fork regression, involving the repair of parental strands and the annealing of nascent daughter strands to form a “chicken foot” or HJ intermediate, is believed to be the initial event in response to replication blockage. BLM has been shown to function in “reverse” branch migration to restart the replication fork though its strand-annealing activity [57]. BLM may also prevent the formation of UFBs (ultrafine anaphase bridges), which correspond to either incompletely replicated DNA sequences or unwound structures and must be resolved before the end of cell division to ensure sister-chromatid disjunction. Most UFBs are of centromeric origin, whereas some UFBs induced by replication stress originate from common fragile sites and telomeres or ribosomal DNA repeats [58, 59]. In cooperation with the primary UFB-binding factor PICH (PLK1-interacting checkpoint helicase), BLM is recruited to UFBs to resolve toxic DNA catenanes [60].DNA repairGiven that BLM interacts with proteins involved in DNA repair and prefers binding to DNA substrates that resemble DNA repair intermediates, it suggests that BLM plays a role in DNA