title: Human nuclease/helicase DNA2 alleviates replication stress by promoting DNA end resection.
abstract: In precancerous and cancerous lesions, excessive growth signals resulting from activation of oncogenes or loss of tumor suppressor genes lead to intensive replication stress, which is recognized by a high level of replication-associated DNA double-strand breaks (DSB). However, the molecular mechanism by which cells alleviate excessive replication stress remains unclear. In this study, we report that the human nuclease/helicase DNA2 facilitates homologous recombination to repair replication-associated DNA DSBs, thereby providing cells with survival advantages under conditions of replication stress. The nuclease activity of DNA2 was required for DSB end resection, which allowed subsequent recruitment of RPA and RAD51 to repair DSBs and restart replication. More importantly, DNA2 expression was significantly increased in human cancers and its expression correlated with patient outcome. Our findings therefore indicate that enhanced activity of DSB resection likely constitutes one mechanism whereby precancerous and cancerous cells might alleviate replication stress.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. gpeng@mdanderson.org
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.forename: Hui
authors.initials: H
authors.lastname: Dai
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Hsieh
authors.forename: Mei-Ren
authors.initials: MR
authors.lastname: Pan
authors.forename: Yun-Yong
authors.initials: YY
authors.lastname: Park
authors.forename: Robert Yu-Lin
authors.initials: RY
authors.lastname: Tsai
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bedrosian
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Ira
authors.forename: Shiaw-Yih
authors.initials: SY
authors.lastname: Lin
mesh_terms: D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases / Q000502:physiology*; D004260:DNA Repair; D004261:DNA Replication; D006657:Histones / Q000032:analysis; D059765:Homologous Recombination; D006801:Humans
chemical_list: C468783:H2AX protein, human; D006657:Histones; D004265:DNA Helicases; C509908:DNA2 protein, human