RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells

Jennifer M. Mason, Kritika Dusad, William Douglass Wright, Jennifer Grubb, Brian Budke, Wolf Dietrich Heyer, Philip P. Connell, Ralph R. Weichselbaum, Douglas K. Bishop

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

The RAD54 family DNA translocases have several biochemical activities. One activity, demonstrated previously for the budding yeast translocases, is ATPase-dependent disruption of RAD51-dsDNA binding. This activity is thought to promote dissociation of RAD51 from heteroduplex DNA following strand exchange during homologous recombination. In addition, previous experiments in budding yeast have shown that the same activity of Rad54 removes Rad51 from undamaged sites on chromosomes; mutants lacking Rad54 accumulate nonrepair-associated complexes that can block growth and lead to chromosome loss. Here, we show that human RAD54 also promotes the dissociation of RAD51 from dsDNA and not ssDNA. We also show that translocase depletion in tumor cell lines leads to the accumulation of RAD51 on chromosomes, forming complexes that are not associated with markers of DNA damage. We further show that combined depletion of RAD54L and RAD54B and/or artificial induction of RAD51 overexpression blocks replication and promotes chromosome segregation defects. These results support a model in which RAD54L and RAD54B counteract genome-destabilizing effects of direct binding of RAD51 to dsDNA in human tumor cells. Thus, in addition to having genome-stabilizing DNA repair activity, human RAD51 has genome-destabilizing activity when expressed at high levels, as is the case in many human tumors.

Original languageEnglish (US)
Pages (from-to)3180-3196
Number of pages17
JournalNucleic Acids Research
Volume43
Issue number6
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Genetics

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    Mason, J. M., Dusad, K., Wright, W. D., Grubb, J., Budke, B., Heyer, W. D., Connell, P. P., Weichselbaum, R. R., & Bishop, D. K. (2015). RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells. Nucleic Acids Research, 43(6), 3180-3196. https://doi.org/10.1093/nar/gkv175