Postreplication checkpoint

Postreplication checkpoint

When the genomic DNA of eukaryotic cells becomes damaged by spontaneous processes, chemical mutagens, or sunlight exposure, the replication of damaged DNA triggers a cellular response called a postreplication checkpoint.^[1] This response prevents cell cycle progression until postreplication repair processes are completed, and may control the activity of these DNA repair pathways.^[2] In cell types that execute S phase before mitosis, such as fission yeast and human cells, the postreplication checkpoint makes time for repair by delaying the onset of mitosis. In cell types where mitosis and S phase are concurrent, such as budding yeast, the postreplication checkpoint delays the progress of mitosis at metaphase.^[3]

The chk1 gene is required to mediate the postreplication checkpoint and is conserved in yeast and humans. Fission yeast cells in which the chk1 gene has been disrupted progress normally through the cell cycle after exposure to UV radiation until they have carried damaged DNA through S-phase and the subsequent mitosis, at which point cells begin to die and exhibit gross chromosomal damage.^[1] The BRCA1 tumor suppressor plays a role in the activation of human chk1,^[4] therefore the postreplication checkpoint may prevent the genetic changes that lead to cancer.

The signal for activation

A number of genes required for the postreplication checkpoint encode proteins that recognize single-stranded DNA and the 5' end of transitions between single-stranded DNA and double-stranded DNA.^[5][6] These structure are known to be generated in two different ways during S phase. The replication of DNA containing damaged bases leaves gaps in the newly-synthesized DNA strand,^[7][8] and the replication of nicked or gapped DNA creates double-strand breaks. Both structures are thought to activate the postreplication checkpoint.

References

1. ^ ^{a b} Callegari AJ, Kelly TJ. UV irradiation induces a postreplication DNA damage checkpoint. Proc Natl Acad Sci U S A 2006; 103:15877-82
2. ^ Callegari AJ, Kelly TJ. Shedding light on the DNA damage checkpoint. Cell Cycle 2007; 6:660-6.
3. ^ Cohen-Fix O, Koshland D. The anaphase inhibitor of Saccharomyces cerevisiae Pds1p is a target of the DNA damage checkpoint pathway. Proc Natl Acad Sci U S A 1997; 94:14361-6.
4. ^ Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet 2002; 30:285-9.
5. ^ Ellison V, Stillman B. Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5' recessed DNA. PLoS Biol 2003; 1:E33.
6. ^ Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 2003; 300:1542-8.
7. ^ Lehmann AR. Post-replication repair of DNA in ultraviolet-irradiated mammalian cells. No gaps in DNA synthesized late after ultraviolet irradiation. Eur J Biochem 1972; 31:438-45.
8. ^ Lopes M, Foiani M, Sogo JM. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol Cell 2006; 21:15-27.

External links

• Expert commentary on Faculty of 1000
• Commentary in Nature
• Commentary in Journal of Investigative Dermatology