This is an important paper indicating the molecular biology of cancer of the breast.
The amino (N) terminus of BRCA 1 has a RING domain that interacts with ubiquitin-conjugating enzymes and is required for its ubiquitin ligase activity. Ligase enzymes catalyse the joining together ofmolecules of two substances and with a breaking of a diphopsatebond in a nucleoside triphosphate. They used to be called synthetase.
Many disease-causing mutations are found within this region, and loss of the ligase activity is associated with suscepti¬bility to breast cancer. BRCAl¬ dependent ubiquitin conjugates are generated at sites of DNA damage repair in human cells..
BRCAl recruitment to chromatin at sites of DNA damage occurs through a complex cascade of protein modifications and interac¬tions, and BRCAl is the third in a sequence of ubiquitin ligases recruited to such sites. Binding of the mediator of DNA damage checkpoint 1 (MDCl) protein to the phosphorylated tail of histone H2AX (‘)’-H2AX) at sites of DNA breakage recruits the ubiquitin ligase RNF8, which generates ubiquitin chains bound by RAP80:ABRAl, which in turn recruits BRCAl through its carboxy (C) terminus 14-20. The activity of the second ubiquitin ligase, RNF168, maintains the ubiquitin chain signal initiated by RNF8 and thus helps retain BRCAl at these sites.
Mutations in BRCAl are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase..
In this paper Morris and colleagues report that BRCA1 is modified by small ubiquitin-like modifier (SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUM01, SUM02/3 and the SUMO-conjugating enzyme Ubc9. PI AS SUMO E3 ligases eo-localize with and modulate SUMO modification of BRCA 1, and are required for BRCA 1 ubiquitin ligase activity in cells.
PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.
Morris JR et al 2009 The SUMO modification pathway is involved in the BRCA 1 response to genotoxic stress Nature vol 462 pp 886-890
- Martin Eastwood