RNF8

Description

The RNF8 (ring finger protein 8) is a protein-coding gene located on chromosome 6.

E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair.

== Function == The protein encoded by this gene contains a RING finger motif and an FHA domain. This protein has been shown to interact with several class II ubiquitin-conjugating enzymes (E2), including UBE2E1/UBCH6, UBE2E2, and UBE2E3, and may act as a ubiquitin ligase (E3) in the ubiquitination of certain nuclear proteins. Alternatively spliced transcript variants encoding distinct isoforms have been reported. RNF8 promotes repair of DNA damage through three DNA repair pathways: homologous recombinational repair (HRR), non-homologous end joining (NHEJ), and nucleotide excision repair (NER). DNA damage is considered to be the primary cause of cancer, and deficiency in DNA repair can cause mutations leading to cancer. A deficiency in RNF8 predisposes mice to cancer.

== Chromatin remodeling == After the occurrence of a double-strand break in DNA, the chromatin needs to be relaxed to allow DNA repair, either by HRR or by NHEJ. There are two pathways that result in chromatin relaxation, one initiated by PARP1 and one initiated by γH2AX (the phosphorylated form of the H2AX protein) (see Chromatin remodeling). Chromatin remodeling initiated by γH2AX depends on RNF8, as described below.

RNF8, also known as RING finger protein 8 or RING-type E3 ubiquitin transferase RNF8, is an E3 ubiquitin-protein ligase that plays a crucial role in DNA damage signaling. It achieves this through two distinct mechanisms:

Lys-63-linked ubiquitination of histones H2A and H2AX: RNF8 catalyzes the attachment of ubiquitin chains to these histones using a Lys-63 linkage. This modification promotes the recruitment of DNA repair proteins to sites of double-strand breaks (DSBs) and facilitates the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). It also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites.
Lys-48-linked ubiquitination for protein degradation: RNF8 can also catalyze the formation of Lys-48-linked ubiquitin chains, which mark proteins for degradation by the proteasome. This mechanism is involved in removing certain proteins from DNA damage sites, such as KU80/XRCC5, JMJD2A/KDM4A, and POLD4/p12.

RNF8 is recruited to DNA damage sites by ATM-phosphorylated MDC1. It also functions in interstrand cross-link (ICL) repair by ubiquitinating histones H2A and H2AX, leading to the recruitment of the Fanconi anemia (FA) complex. Furthermore, RNF8 is involved in ATM activation by promoting histone H2B ubiquitination, which indirectly triggers histone H4 Lys-16 acetylation (H4K16ac), creating an environment conducive to ATM kinase activation.

Beyond its role in DNA damage response, RNF8 plays a part in higher-order chromatin structure, mediating chromatin decondensation. It is also required for proper exit from mitosis and may regulate cytokinesis. RNF8's activities in telomere maintenance and class switch recombination contribute to its broader role in maintaining genomic stability.

RNF8 is also known as hRNF8.

Associated Diseases

WES Whole Exome Sequencing