The Functions of DNA Damage Factor RNF8 in the Pathogenesis and Progression of Cancer

Abstract

The really interesting new gene (RING) finger protein 8 (RNF8) is a central factor in DNA double strand break (DSB) signal transduction. DSB damage is the most toxic type of DNA damage to cells and is related to genomic instability. Multiple roles for RNF8 have been identified in DNA damage response as well as in other functions, such as telomere protection, cell cycle control and transcriptional regulation. These functions are closely correlated to tumorigenesis and cancer progression. Indeed, deficiency of RNF8 caused spontaneous tumorigenesis in a mouse model. Deciphering these mechanisms of RNF8 may shed light on strategies for cancer treatment. In this review, we summarize the current understanding of both classical and nonclassical functions of RNF8, and discuss its roles in the pathogenesis and progression of tumor.

Keywords: DSB; RNF8; cell cycle; telomere; transcriptional regulation; tumor.

Figure 1

The role of RNF8 involves in DSB signaling pathway. The MRN complex senses the DSB and recruits ATM. Upon being activated by autophosphorylation, ATM phosphorylates histone H2AX (γH2AX). MDC1 recognizes γH2AX and is phosphorylated by ATM and then acts as a platform that recruits RNF8. RNF8 binds CHD4 to decondense chromatin and allow RNF8 to access H2A. RNF8 promotes monoubiquitination of H2A/H2AX with the help of DYRK2. Upon phosphorylation by ATM, L3MBTL2 associates with MDC1 and is polyubiquitinated by RNF8. Ubiquitinated L3MBTL2 recruits RNF168, which amplifies the polyubiquitination chain of H2A/H2AX. After being stabilized by RNF8, JMJD1C facilitates the demethylation and ubiquitination of MDC1. This effect promotes the recognition of RAP80 to ubiquitination signal. Subsequently, BRCA1 complex is recruited to RAP80 via CCDC98 and induces the downstream HR repair by Rad51 through PALB2. The RNF8-UBC13 complex also catalyzes K48 polyubiquitination of JMJD2A. The degradation of JMJD2A promotes the interaction of 53BP1 with methylated H3/H4 and induces NHEJ repair. 53BP1 is also recruited to K15 polyubiquitinated H2A conjugated by RNF8 and RNF168. The RNF8 partner DYRK2 also facilitates the recruitment of 53BP1 to DSB sites.

Figure 2

The dual impact of RNF8 on cancer. (1) RNF8 promotes K48 polyubiquitination and degradation of N1ICD, thereby causing the downregulation of Notch signaling. RNF8 also transduces DSB signaling to repair DNA damage. These two pathways help to restrain the tumorigenesis of breast cancer. (2) With EGF- or DSB-inducing drug treatment, RNF8 conjugates K63 polyubiquitination of Twist, which promotes Twist stabilization and activation. This induces CSC selfrenewal and increases cell mobility to render chemoresistance and metastasis capacity to TNBC cells. (3) RNF8 interacts with and promotes monoubiquitination of ERα which partially contributes to the stabilization of ERα. RNF8 enhances the transactivation of ERα and upregulates ERα target genes with estrogen treatment, which increases breast cancer proliferation.