FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation

Abstract

Nucleotide excision repair (NER) is critical for the repair of DNA lesions induced by UV radiation, but its contribution in replicating cells is less clear. Here, we show that dual incision by NER endonucleases, including XPF and XPG, promotes the S-phase accumulation of the BRCA1 and Fanconi anemia–associated DNA helicase FANCJ to sites of UV-induced damage. FANCJ promotes replication protein A phosphorylation and the arrest of DNA synthesis following UV irradiation. Interaction defective mutants of FANCJ reveal that BRCA1 binding is not required for FANCJ localization, whereas interaction with the mismatch repair (MMR) protein MLH1 is essential. Correspondingly, we find that FANCJ, its direct interaction with MLH1, and the MMR protein MSH2 function in a common pathway in response to UV irradiation. FANCJ-deficient cells are not sensitive to killing by UV irradiation, yet we find that DNA mutations are significantly enhanced. Thus, we considered that FANCJ deficiency could be associated with skin cancer. Along these lines, in melanoma we found several somatic mutations in FANCJ, some of which were previously identified in hereditary breast cancer and Fanconi anemia. Given that, mutations in XPF can also lead to Fanconi anemia, we propose collaborations between Fanconi anemia, NER, and MMR are necessary to initiate checkpoint activation in replicating human cells to limit genomic instability.

hMSH5 Facilitates the Repair of Camptothecin-induced Double-strand Breaks through an Interaction with FANCJ

“…Recent studies suggested that the interaction between FANCJ and hMLH1 plays a role in appropriate interstrand cross-link repair damage signaling, and hMSH2 depletion suppressed the interstrand cross-link repair sensitivity exerted by cells lacking the interaction between FANCJ and hMLH1 (56,57). In the present study, we found that the interaction between hMSH5 and FANCJ plays important roles in cellular defense to CPT challenge.…”

Crosstalk between BRCA‐Fanconi anemia and mismatch repair pathways prevents MSH2‐dependent aberrant DNA damage responses

“…FANCD2-FAN1, BRCA1, and FANCJ interact with MLH1, and SLX4/FANCP interacts with MSH2 (Wang et al , 2000; Svendsen et al , 2009; Kratz et al , 2010; Liu et al , 2010; O'Donnell & Durocher, 2010; Shereda et al , 2010; Smogorzewska et al , 2010; Yoshikiyo et al , 2010). Moreover, the MMR pathway activates the BRCA-FA pathway, inducing FANCD2 monoubiquitination and localization of FANCJ to sites of DNA crosslinks (Huang et al , 2011; Williams et al , 2011; Suhasini et al , 2013; Guillemette et al , 2014). In this study, we provide further evidence that crosstalk between BRCA-FA and MMR pathways is critical for coordinating the DNA damage response.…”

“…Moreover, we found that FANCJ binding to the MMR protein MLH1 is essential for ICL repair (Peng et al , 2007; Cantor & Xie, 2010; Xie et al , 2010). Further suggesting a functional connection between these pathways, MMR proteins activate the BRCA-FA pathway, including the promotion of FANCD2 monoubiquitination (Huang et al , 2011; Williams et al , 2011) and also localize FANCJ to sites of ICLs and DNA crosslinks induced by ultraviolet light (Suhasini et al , 2013; Guillemette et al , 2014). …”

FANCJ at the FORK

“…In contrast, FANCJ deficient cells have minor sensitivity to agents that induce DNA double strand breaks (DSBs), such as ionizing radiation (IR) and camptothecin. The mild sensitivity to DSB-inducing agents and lack of sensitivity to ultraviolet light (UV) irradiation distinguishes FANCJ deficient cells from BRCA-deficient cells 8,18,25–27 (see Supplemental Table 1). Nevertheless, IR-induced DNA double strand breaks and UV-induced DNA intrastrand crosslinks are repaired with reduced kinetics in BRCA1- or FANCJ-deficient cells 17,18,28 .…”