Biological Pathway
The pathway of HDR is not totally enlightened yet (March 2008). Though there are a lot of experimental results which point to the validity of certain models. Generally accepted is the phosphorylation of histone H2AX (noted as γH2AX) within seconds after occurrence of the damage. H2AX is phosphorylated widely in the surrounding area of the damage and not only at the precise location. Therefore γH2AX is suggested to function as an adhesive component to attract proteins to the damaged location. A variety of research groups suggest that the phosphorylation of H2AX is done by ATM and ATR in cooperation with MDC1. Before or meanwhile H2AX is involved in the repair pathway the MRN complex (which consists of Mre11, Rad50 and NBS1) is suggested to stick at the broken DNA ends and other MRN complexes to keep the broken ends together. The act of the MRN complex might prevent chromosomal breaks. Somewhat further in the process the DNA ends are processed so unnecessary left overs of chemical groups etc. are removed and single strand overhands a formed. In the meanwhile, from the beginning, every piece of single stranded DNA is covered by the protein RPA (Replication Protein A). The function of RPA is likely to keep the single stranded DNA piece stable until the complementary piece is resynthesized by a polymerase. After this, Rad51 replaces RPA and forms filaments on the DNA. Together with BRCA2 (Breast Cancer Associated) it couples a complementary DNA piece which invades the broken DNA strand to form a template for the polymerase. The polymerase is held on the DNA strand by PCNA (Proliferating Cell Nuclear Antigen). PCNA forms typical patterns in the nucleus of the cell by which the current cell cycle can be determined. The polymerase synthesizes the missing part of the broken strand. When the broken strand is rebuild both strands need to uncouple again. Multiple ways of "uncoupling" are suggested though there is no evidence yet to discard or accept a model (March 2008). After the strands are separated the process is done.
The co localization of Rad51 with the damage is accepted to be the definite point where HDR is initiated instead of NHEJ. For NHEJ the Ku complex (Ku70 and Ku80) is the point to accept where NHEJ is initiated instead of HDR.
HDR and NHEJ repair double strand breaks. Other mechanisms such as NER (Nucleotide Excision Repair), BER (Base Excision Repair) and MMR recognise lesions and replace them via single strand perturbation.
Read more about this topic: Homology Directed Repair
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