Oncotarget

Research Papers:

Rad18 is required for functional interactions between FANCD2, BRCA2, and Rad51 to repair DNA topoisomerase 1-poisons induced lesions and promote fork recovery

Kaushlendra Tripathi _, Chinnadurai Mani, David W Clark and Komaraiah Palle

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Oncotarget. 2016; 7:12537-12553. https://doi.org/10.18632/oncotarget.7247

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Abstract

Kaushlendra Tripathi1, Chinnadurai Mani1, David W Clark1, Komaraiah Palle1

1Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, 36604, USA

Correspondence to:

Komaraiah Palle, e-mail: kpalle@health.southalabama.edu

Keywords: Rad18, FANCD2, Rad51, BRCA2, DNA topoisomerase 1

Received: October 27, 2015    Accepted: January 27, 2016    Published: February 08, 2016

ABSTRACT

Camptothecin (CPT) and its analogues are chemotherapeutic agents that covalently and reversibly link DNA Topoisomerase I to its nicked DNA intermediate eliciting the formation of DNA double strand breaks (DSB) during replication. The repair of these DSB involves multiple DNA damage response and repair proteins. Here we demonstrate that CPT-induced DNA damage promotes functional interactions between BRCA2, FANCD2, Rad18, and Rad51 to repair the replication-associated DSB through homologous recombination (HR). Loss of any of these proteins leads to equal disruption of HR repair, causes chromosomal aberrations and sensitizes cells to CPT. Rad18 appears to function upstream in this repair pathway as its downregulation prevents activation of FANCD2, diminishes BRCA2 and Rad51 protein levels, formation of nuclear foci of all three proteins and recovery of stalled or collapsed replication forks in response to CPT. Taken together this work further elucidates the complex interplay of DNA repair proteins in the repair of replication-associated DSB.


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