Abstract 3380: BRIP1/FANCJ is vital for efficient response to and repair of replication-associated DNA damage

Abstract

Abstract BRCA1-Interacting Protein 1 (BRIP1), a DNA helicase and tumor suppressor also known as FANCJ, is implicated in breast and ovarian cancers as well as the genetic instability syndrome Fanconi anemia (FA) which predisposes patients to multiple neoplasms. This study investigates the role of FANCJ in repair of replication-associated DNA damage which can lead to DNA strand breaks, chromosomal instability, and tumorigenesis. FANCJ has long been known to function in repair of DNA crosslinks; however, its role in protecting cells from replication-associated DNA damage is less well known. We have shown that loss of FANCJ sensitizes cells to damage caused by compounds that block DNA replication, such as hydroxyurea (HU) and the topoisomerase I poison camptothecin (CPT). Loss of FANCJ disrupts the cell's response to replication-associated DNA damage by impairing Chk1 and Chk2 phosphorylation and stability and activation of multiple DNA repair proteins. FANCJ-deficient cells exposed to low levels of CPT failed to progress through S-phase indicating that FANCJ is important for intra-S phase DNA damage checkpoint and recovery from replication fork blocks. FANCJ depletion leads to a 90% decrease in homologous recombination repair in assays designed to measure repair of DNA double strand breaks as well as a loss of expression of repair-associated proteins and DNA repair foci in response to damage from HU and CPT. Loss of FANCJ impairs DNA replication and leads to accumulation of gross chromosomal aberrations. Importantly, some of the DNA damage response functions of FANCJ are independent of its helicase activity, as a helicase-deficient mutant is able to compensate for loss of FANCJ in activation and stability of FANCD2 and other HR proteins. Collectively our findings indicate a novel role for FANCJ as a key regulator of the DNA damage response to errors in DNA replication potentially leading to mutagenesis and tumorigenesis. Citation Format: David W. Clark, Chinnadurai Mani, Komariah Palle. BRIP1/FANCJ is vital for efficient response to and repair of replication-associated DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3380.