Note for: Genetic analysis of the DNA-dependent protein kinase reveals an inhibitory role of Ku in late S-G2 phase DNA double-strand break repair

Note for: Genetic analysis of the DNA-dependent protein kinase reveals an inhibitory role of Ku in late S-G2 phase DNA double-strand break repair

(doi: 10.1074/jbc.M106295200)

DNA-PK domains;

1. Ku70/80 binding domain Ku70/Ku80

2. Catalytic subunit

Previous study showed Ku70(-/-) --> Rad54-dependent radio-resistant on S-G2 phase cells.

Ku70(-/-)Rad54(-/-) showed radioresistance.

DSB repairs in vertebrates have two "complementary" DSB repair; NHEJ and HR.

HR requires Rad52 epistasis group -- Rad51 and Rad54

NHEJ requires DNA-PK, XRCC4, and Lig4.

Ku70/80 binds to DSB --> recruit DNA-PK-->kinase activity occurs

Mice lacking DNA-PK-->increase radiosensitivity and defect in V(D)J recombination.

Though Ku involved with NHEJ but defect of Ku in mice showed more effect that DNA-PK(-/-)-->conferring the other important functions Ku comparing with DNA-PKs (less effect when KO).

Observation has been raised from the complementary to compete for each other. This hypothesis came from the biochemical study which indicates the competitive binding of proteins from HR/NHEJ at the DNA lesion.

Ku has been proposed to play role as switch controlling which leading the cells to fix DSB by NHEJ.

Ku70(-/-) – more sensitive toward IR in early G1-S phase since the DSB repair relies on NHEJ; comparing to late S-G2 phase where HR is majorly used – Ku70(-/-) is less sensitive.

There is the difference between mammalian and DT40 -->late S-G2--> in chicken HR is more important to fix DSB rather than in mammalian cell lines.

Because of the discrepancies between DT40 and mammalian cell lines-->care should be taken which cell line should be used to study on what.

The author pointed out not only the cell cycle play role to determine which pathway is used to fix DSB-->cell type also affect the competition between HR and NHEJ-->to me this means that it does not fix that G2-S must be fixed by HR--cell type is another factor which should take into consideration that NHEJ might be the major pw to fix the DSB.