The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase

Harrigan, Jeanine A.; Wilson, David M.; Prasad, Rajendra; Opresko, Patricia L.; Beck, Gad; May, Alfred; Wilson, S.H.; Bohr, Vilhelm A.

doi:10.1093/nar/gkj475

Cited by 118 publications

(127 citation statements)

References 45 publications

(48 reference statements)

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…65 In addition, POLB (8p11) and NAIL2 (8p23) are also involved in DNA repair as a key element in BER, and WRN likely acts cooperatively with POLB via its helicase and exonuclease activity. 66 It can be assumed that all these 3 interacting genes will be co-deleted in many cancers with 8p deletions. CGH and NGS data suggest, that at least 27-55% of 8p deleted cancers extend from 8p11-8p23.…”

Section: Discussionmentioning

confidence: 99%

8p deletion is strongly linked to poor prognosis in breast cancer

Lebok

Mittenzwei

Kluth

et al. 2015

Cancer Biology & Therapy

View full text Add to dashboard Cite

Deletions of chromosome 8p occur frequently in breast cancers, but analyses of its clinical relevance have been limited to small patient cohorts and provided controversial results. A tissue microarray with 2,197 breast cancers was thus analyzed by fluorescence in-situ hybridization using an 8p21 probe in combination with a centromere 8 reference probe. 8p deletions were found in 50% of carcinomas with no special type, 67% of papillary, 28% of tubular, 37% of lobular cancers and 56% of cancers with medullary features. Deletions were always heterozygous. 8p deletion was significantly linked to advanced tumor stage (P < 0.0001), high-grade (P < 0.0001), high tumor cell proliferation (Ki67 Labeling Index; P < 0.0001), and shortened overall survival (P < 0.0001). For example, 8p deletion was seen in 32% of 290 grade 1, 43% of 438 grade 2, and 65% of 427 grade 3 cancers. In addition, 8p deletions were strongly linked to amplification of MYC (P < 0.0001), HER2 (P < 0.0001), and CCND1 (p D 0.001), but inversely associated with ER receptor expression (p D 0.0001). Remarkably, 46.5% of 8p-deleted cancers harbored amplification of at least one of the analyzed genes as compared to 27.5% amplifications in 8p-non-deleted cancers (P < 0.0001). In conclusion, 8p deletion characterizes a subset of particularly aggressive breast cancers. As 8p deletions are easy to analyze, this feature appears to be highly suited for future DNA based prognostic breast cancer panels. The strong link of 8p deletion with various gene amplifications raises the possibility of a role for regulating genomic stability.

show abstract

Section: Discussionmentioning

confidence: 99%

8p deletion is strongly linked to poor prognosis in breast cancer

Lebok

Mittenzwei

Kluth

et al. 2015

Cancer Biology & Therapy

View full text Add to dashboard Cite

show abstract

“…Recently, the exonucleolytic capacity of WRN has been assessed as a function of the pol ß interaction. Specifically, WRN exonuclease activity can act in conjunction with pol ß, a protein with no intrinsic 3'-5' proofreading activity [89]. WRN also partners with PARP1, the DNA singlestrand nick sensing protein [87].…”

Section: Gap Tailoringmentioning

confidence: 99%

“…Whereas phosphorylation prevents Fen1-mediated stimulation of PCNA, acetylation by p300 appears to reduce the ability of Fen1 to bind to DNA and to function as a nuclease, with no effect on its PCNA interaction (Table III). WRN also stimulates strand displacement activities of pol ß [88,89] and is included herein as a gap tailoring protein since it removes 3'lesions via its 3'⇒5' exonuclease activity [124] and acts as a participant in promoting long-patch BER. Similar to Fen1, phosphorylation of WRN decreases its catalytic activity (Table III).…”

Section: Post-translational Modifications Of Ber Gap Tailoring Proteinsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

386

374

View full text Add to dashboard Cite

Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

show abstract

“…WRN exonuclease can also function as an extrinsic proofreader for DNA polymerase β during base excision repair (BER) (Harrigan et al 2006). Studies based upon the X-ray crystal structure of human WRN exonuclease domain give a firm assignment of editing functionality (Perry et al 2006), akin to endprocessing activities of other members of the DnaQ family.…”

Section: Wrnmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

View full text Add to dashboard Cite

Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

show abstract

The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase

Cited by 118 publications

References 45 publications

8p deletion is strongly linked to poor prognosis in breast cancer

8p deletion is strongly linked to poor prognosis in breast cancer

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Contact Info

Product

Resources

About