Human RecQ Helicases in DNA Repair, Recombination, and Replication

Croteau, Deborah L.; Popuri, Venkateswarlu; Opresko, Patricia L.; Bohr, Vilhelm A.

doi:10.1146/annurev-biochem-060713-035428

Cited by 481 publications

(541 citation statements)

References 301 publications

(383 reference statements)

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“…BLM is an ATP-dependent 3 0 -5 0 DNA helicase involved in unwinding a variety of DNA substrates that can arise during DNA replication and repair (1)(2)(3)(4)(5). BLM has important roles in the initiation and regulation of homologous recombination (HR) repair of double-strand breaks (DSB).…”

Section: Introductionmentioning

confidence: 99%

“…BLM is also part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, PMS2, and the RAD50-MRE11-NBS1 protein complex (6). In addition to its DNA repair function, BLM is involved in the processing of stalled replication forks during replication and in telomere maintenance in cells (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Bloom syndrome is characterized by cancer predisposition, growth retardation, immunodeficiency, sunlight hypersensitivity, and impaired fertility (7). BLM germ-line mutation results in dramatic reduction in BLM mRNA levels and BLM protein expression, leading to extensive chromosomal instability manifested classically as excessive frequency of sister chromatid exchanges (SCE) in Bloom syndrome cells (1)(2)(3)(4)(5). Patients with Bloom syndrome are prone to develop leukemia, lymphomas, and a variety of epithelial cancers, including breast cancers (7).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer

Arora

Abdel-Fatah

Agarwal

et al. 2015

Molecular Cancer Therapeutics

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Bloom syndrome helicase (BLM) has key roles in homologous recombination repair, telomere maintenance, and DNA replication. Germ-line mutations in the BLM gene causes Bloom syndrome, a rare disorder characterized by premature aging and predisposition to multiple cancers, including breast cancer. The clinicopathologic significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n ¼ 1,950) and validated in an external dataset of 2,413 tumors. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1,650 breast tumors. BLM mRNA overexpression was significantly associated with high histologic grade, larger tumor size, estrogen receptor-negative (ER À ), progesterone receptor-negative (PR À ), and triple-negative phenotypes (ps < 0.0001). BLM mRNA overexpression was also linked to aggressive molecular phenotypes, including PAM50.Her2 (P < 0.0001), PAM50. Basal (P < 0.0001), and PAM50.LumB (P < 0.0001) and Genufu subtype (ER þ /Her2 À /high proliferation; P < 0.0001). PAM50. LumA tumors and Genufu subtype (ER þ /Her2 À /low proliferation) were more likely to express low levels of BLM mRNA (ps < 0.0001). Integrative molecular clusters (intClust) intClust.1 (P < 0.0001), intClust.5 (P < 0.0001), intClust.9 (P < 0.0001), and intClust.10 (P < 0.0001) were also more likely in tumors with high BLM mRNA expression. BLM mRNA overexpression was associated with poor breast cancer-specific survival (BCSS; ps < 0.000001). At the protein level, altered subcellular localization with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS. This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer

Arora

Abdel-Fatah

Agarwal

et al. 2015

Molecular Cancer Therapeutics

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“…One of the most important and well-studied UFB-binding proteins recruited by PICH is the Bloom’s syndrome helicase BLM [6,19]. BLM is a RecQ family helicase that can efficiently unwind a variety of DNA structures [55]. BLM interacts with topoisomerase IIIα, RMI1 and RMI2 to form the BTR complex that mediates the dissolution of double HJs.…”

Section: Proteins That Recognize and Process Hr-ufbsmentioning

confidence: 99%

A new class of ultrafine anaphase bridges generated by homologous recombination

Chan

West

2018

Cell Cycle

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Ultrafine anaphase bridges (UFBs) are a potential source of genome instability that is a hallmark of cancer. UFBs can arise from DNA catenanes at centromeres/rDNA loci, late replication intermediates induced by replication stress, and DNA linkages at telomeres. Recently, it was reported that DNA intertwinements generated by homologous recombination give rise to a new class of UFBs, which have been termed homologous recombination ultrafine bridges (HR-UFBs). HR-UFBs are decorated with PICH and BLM in anaphase, and are subsequently converted to RPA-coated, single-stranded DNA bridges. Breakage of these sister chromatid entanglements leads to DNA damage that can be repaired by non-homologous end joining in the next cell cycle, but the potential consequences include DNA rearrangements, chromosome translocations and fusions. Visualisation of these HR-UFBs, and knowledge of how they arise, provides a molecular basis to explain how upregulation of homologous recombination or failure to resolve recombination intermediates leads to the development of chromosomal instability observed in certain cancers.

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“…One of such activities is that of DNA helicases that recognize and process specific toxic structures generated during replication. The RECQ family of helicases has been particularly linked to RS and disease [51]. The different members of the family show multiple roles in replication during initiation, elongation, lagging strand processing and fork repair.…”

Section: Rs As a Fuel Of Tumorogenesismentioning

confidence: 99%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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Human RecQ Helicases in DNA Repair, Recombination, and Replication

Cited by 481 publications

References 301 publications

Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer

Transcriptomic and Protein Expression Analysis Reveals Clinicopathological Significance of Bloom Syndrome Helicase (BLM) in Breast Cancer

A new class of ultrafine anaphase bridges generated by homologous recombination

Replication stress and cancer: It takes two to tango

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