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PMID: 22491672 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Human nuclease/helicase DNA2 alleviates replication stress by promoting DNA end resection.

Cancer research ·Vol. 72 ·No. 11 ·2012-06-01 ·Pages 2802-13

Peng G, Dai H, Zhang W, Hsieh HJ, Pan MR, Park YY, Tsai RY, Bedrosian I, Lee JS, Ira G, Lin SY

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.

MeSH Terms
DNA Breaks, Double-Stranded DNA Helicases/physiology DNA Repair DNA Replication Histones/analysis Homologous Recombination Humans
Chemicals
H2AX protein, human Histones DNA Helicases DNA2 protein, human
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Peng Guang
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. [email protected]
Dai Hui
Zhang Wei
Hsieh Hui-Ju
Pan Mei-Ren
Park Yun-Yong
Tsai Robert Yu-Lin
Bedrosian Isabelle
Lee Ju-Seog
Ira Grzegorz
Lin Shiaw-Yih
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Article Info
Journal
Cancer research
Abbr.
Cancer Res
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-11-3152
Email
[email protected]
Published
2012-06-01
Epub
2012-00-09
Pages
2802-13
Language
English
Region
United States
NLM ID
2984705R
PMCID
PMC3367086
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA112291 · United States
NCI NIH HHS · R01 CA181663 · United States
NIGMS NIH HHS · R01 GM080600-05 · United States
NCI NIH HHS · K99 CA149186-01A1 · United States
NCI NIH HHS · R01 CA112291-05 · United States
NIGMS NIH HHS · R01 GM080600 · United States
NCI NIH HHS · K99 CA149186 · United States
NCI NIH HHS · K99 CA149186-02 · United States
NIGMS NIH HHS · GM080600 · United States
External Links
PubMed source DOI: 10.1158/0008-5472.CAN-11-3152 PMC Full Text View journal details
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