| Autor: |
Breslin, Claire, Mani, Rajam S, Fanta, Mesfin, Hoch, Nicolas, Weinfield, Michael, Caldecott, Keith W |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| ISSN: |
1083-351X |
| Popis: |
The scaffold protein X-ray repair cross-complementing 1 (XRCC1)interacts with multiple enzymes involved in DNA base excision repair and single-strand break repair(SSBR) and is important for genetic integrity and normal neurological\ud function. One of the most important interactions of XRCC1 is that with polynucleotide kinase/phosphatase(PNKP), a dual-function DNA kinase/phosphatase that processes damaged DNA termini and that, if mutated, results in ataxia with oculomotor apraxia 4 (AOA4) and microcephaly with early-onset seizures and developmental delay(MCSZ). XRCC1 and PNKP interact via a high-affinity phosphorylationdependent\ud interaction site in XRCC1 and a fork-head associated domain\ud in PNKP. Here, we identified using biochemical and biophysical approaches a second PNKP interaction site in XRCC1 that binds PNKP with lower affinity and independently of XRCC1 phosphorylation. However, this interaction nevertheless stimulated PNKP activity and promoted SSBR\ud and cell survival. The low-affinity interaction site required the highly conserved REV1-interacting (RIR)\ud motif in XRCC1 and included three critical and evolutionarily invariant phenylalanine residues. We propose\ud a bipartite interaction model in which the previously identified highaffinity interaction acts as a molecular tether, holding XRCC1 and PNKP together and thereby\ud promoting the low-affinity interaction identified here, which then stimulates PNKP directly. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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