Overexpression of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability

Schild, David; Wiese, Claudia

doi:10.1093/nar/gkp1063

Title: Overexpression of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability

Journal Article · 25 November 2009 · Nucleic Acids Research

DOI: https://doi.org/10.1093/nar/gkp1063 · OSTI ID:1625459

Schild, David ^[1]; Wiese, Claudia ^[2]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); DOE/OSTI
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

RAD51, a key protein in the homologous recombinational DNA repair (HRR) pathway, is the major strand-transferase required for mitotic recombination. An important early step in HRR is the formation of single-stranded DNA (ss-DNA) coated by RPA (a ss-DNA-binding protein). Displacement of RPA by RAD51 is highly regulated and facilitated by a number of different proteins known as the ‘recombination mediators’. To assist these recombination mediators, a second group of proteins also is required and we are defining these proteins here as ‘recombination co-mediators’. Defects in either recombination mediators or co-mediators, including BRCA1 and BRCA2, lead to impaired HRR that can genetically be complemented for (i.e. suppressed) by overexpression of RAD51. Defects in HRR have long been known to contribute to genomic instability leading to tumor development. Since genomic instability also slows cell growth, precancerous cells presumably require genomic re-stabilization to gain a growth advantage. RAD51 is overexpressed in many tumors, and therefore, we hypothesize that the complementing ability of elevated levels of RAD51 in tumors with initial HRR defects limits genomic instability during carcinogenic progression. Of particular interest, this model may also help explain the high frequency of TP53 mutations in human cancers, since wild-type p53 represses RAD51 expression.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1625459

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 4 Vol. 38; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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DNA-binding Domain within the Brh2 N Terminus Is the Primary Interaction Site for Association with DNA Zhou, Qingwen; Kojic, Milorad; Holloman, William K. Journal of Biological Chemistry, Vol. 284, Issue 13 https://doi.org/10.1074/jbc.M809226200	journal	March 2009
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Repression of mutagenesis by Rad51D-mediated homologous recombination Hinz, J. M. Nucleic Acids Research, Vol. 34, Issue 5 https://doi.org/10.1093/nar/gkl020	journal	March 2006
RAD51 localization and activation following DNA damage Tarsounas, Madalena; Davies, Adelina A.; West, Stephen C. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, Vol. 359, Issue 1441 https://doi.org/10.1098/rstb.2003.1368	journal	January 2004
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Functional differences and interactions among the putative RecA homologs Rad51, Rad55, and Rad57. Johnson, R. D.; Symington, L. S. Molecular and Cellular Biology, Vol. 15, Issue 9 https://doi.org/10.1128/MCB.15.9.4843	journal	September 1995
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Chk2 Phosphorylation of BRCA1 Regulates DNA Double-Strand Break Repair Zhang, Junran; Willers, Henning; Feng, Zhihui Molecular and Cellular Biology, Vol. 24, Issue 2 https://doi.org/10.1128/MCB.24.2.708-718.2004	journal	January 2004
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RAD51 Up-regulation Bypasses BRCA1 Function and Is a Common Feature of BRCA1 -Deficient Breast Tumors Martin, Richard W.; Orelli, Brian J.; Yamazoe, Mitsuyoshi Cancer Research, Vol. 67, Issue 20 https://doi.org/10.1158/0008-5472.CAN-07-0290	journal	October 2007
Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance Chan, Norman; Koritzinsky, Marianne; Zhao, Helen Cancer Research, Vol. 68, Issue 2 https://doi.org/10.1158/0008-5472.CAN-07-5472	journal	January 2008
Distinct RAD51 Associations with RAD52 and BCCIP in Response to DNA Damage and Replication Stress Wray, J.; Liu, J.; Nickoloff, J. A. Cancer Research, Vol. 68, Issue 8 https://doi.org/10.1158/0008-5472.CAN-07-6505	journal	April 2008
Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation Hannay, Jonathan A. F.; Liu, Juehui; Zhu, Quan-Sheng Molecular Cancer Therapeutics, Vol. 6, Issue 5 https://doi.org/10.1158/1535-7163.MCT-06-0636	journal	May 2007
Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity Choudhury, Ananya; Zhao, Helen; Jalali, Farid Molecular Cancer Therapeutics, Vol. 8, Issue 1 https://doi.org/10.1158/1535-7163.MCT-08-0959	journal	January 2009
PALB2 Functionally Connects the Breast Cancer Susceptibility Proteins BRCA1 and BRCA2 Zhang, Fan; Fan, Qiang; Ren, Keqin Molecular Cancer Research, Vol. 7, Issue 7 https://doi.org/10.1158/1541-7786.MCR-09-0123	journal	July 2009
Utility of DNA Repair Protein Foci for the Detection of Putative BRCA1 Pathway Defects in Breast Cancer Biopsies Willers, Henning; Taghian, Alphonse G.; Luo, Chen-Mei Molecular Cancer Research, Vol. 7, Issue 8 https://doi.org/10.1158/1541-7786.MCR-09-0149	journal	August 2009
p63 and p73 Transcriptionally Regulate Genes Involved in DNA Repair Lin, Yu-Li; Sengupta, Shomit; Gurdziel, Katherine PLoS Genetics, Vol. 5, Issue 10 https://doi.org/10.1371/journal.pgen.1000680	journal	October 2009
Genes encoding Pir51, Beclin 1, RbAp48 and aldolase b are up or down-regulated in human primary hepatocellular carcinoma Song, Hai World Journal of Gastroenterology, Vol. 10, Issue 4 https://doi.org/10.3748/wjg.v10.i4.509	journal	January 2004
Double Bolt Regulation of Rad51 by p53: A Role for Transcriptional Repression Lazaro-Trueba, Iciar; Arias, Carmen; Silva, Augusto Cell Cycle, Vol. 5, Issue 10 https://doi.org/10.4161/cc.5.10.2764	journal	May 2006

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A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest Feng, Zhihui; Zhang, Junran Nucleic Acids Research, Vol. 40, Issue 2 https://doi.org/10.1093/nar/gkr748	journal	September 2011
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Inhibition of RAD51 by siRNA and Resveratrol Sensitizes Cancer Stem Cells Derived from HeLa Cell Cultures to Apoptosis Ruíz, Graciela; Valencia-González, Heriberto A.; León-Galicia, Ismael Stem Cells International, Vol. 2018 https://doi.org/10.1155/2018/2493869	journal	January 2018
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A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest Feng, Zhihui; Zhang, Junran Nucleic Acids Research, Vol. 40, Issue 2 https://doi.org/10.1093/nar/gkr748	journal	September 2011
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