E3 ubiquitin-protein ligase RNF8; RING finger protein 8 (RNF8, KIAA0646)
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Function
- E3 ubiquitin-protein ligase
- required for assembly of repair proteins to sites of DNA damage
- catalyzes the Lys-63-linked ubiquitination of histone H2A & H2AX
- promotes formation of Lys-63-linked polyubiquitin chains & functions with specific ubiquitin-conjugating UBE2N/UBC13
- substrates that are polyubiquitinated at Lys-63 are usually not targeted for degradation
- autoubiquitinated through Lys-48 & Lys-63 of ubiquitin
- Lys-63 polyubiquitination is mediated by UBE2N
- Lys-29-type polyubiquitination is also observed, but doesn't require its own functional RING-type Zn+2 finger
- ubiquitination of histone H2A requires UBE2N but not MMS2 (UBE2V2)
- catalyzes the Lys-63-linked ubiquitination of PCNA
- may also ubiquitinate histone H2B
- not involved in RXRA ubiquitination by UBE2E2
- protein modification; protein ubiquitination
- following DNA double-strand breaks (DSBs), RNF8 is recruited to sites of damage by ATM-phosphorylated MDC1
- enforces the G2/M DNA damage checkpoint
- controls recruitment of UIMC1-BRCC3 (RAP80-BRCC36) & PAXIP1/PTIP to DNA damage sites following DNA double-strand breaks
- may be required for proper exit from mitosis after spindle checkpoint activation & may regulate cytokinesis
- may play a role in the regulation of RXRA-mediated transcriptional activity
- interacts with class III ubiquitin-conjugating protein E2s, including UBE2E1, UBE2E2, & UBE2E3 & with UBE2N
- interacts with RXRA
- interacts (via FHA domain) with ATM-phosphorylated MDC1
- interacts (via FHA domain) with Thr-4827 phosphorylated HERC2 (via C-terminus)
Structure
- the FHA domain specifically recognizes & binds ATM- phosphorylated MDC1 & Thr-4827 phosphorylated HERC2
- belongs to the RNF8 family
- contains 1 FHA domain
- contains 1 RING-type Zn+2 finger
Compartment
- nucleus, midbody
- following DNA double-strand breaks, recruited to the sites of damage
- during prophase, concomitant with nuclear envelope breakdown, localizes throughout the cell, with a dotted pattern
- in telophase, localizes in the nucleus & also in a discrete dotted pattern in the cytoplasm
- in late telophase & during cytokinesis, localizes in the midbody of the tubulin bridge joining the daughter cells
- does not seem to be associated with condensed chromosomes at any time during the cell cycle
Alternative splicing
- named isoforms=2
- at least one isoform may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay
Expression
- ubiquitous
- highest expression in brain & testis
- lowest expression in peripheral blood cells
- in fetus, highest expression in brain, thymus & liver
- low levels at the G1-S boundary increase in intensity during S phase & until the end of the G2 phase
- abruptly decreases in late mitosis (at protein level)
- barely detectable in anaphase