Abstract:
:The Saccharomyces cerevisiae RAD18 gene is essential for postreplication repair but is not required for homologous recombination (HR), which is the major double-strand break (DSB) repair pathway in yeast. Accordingly, yeast rad18 mutants are tolerant of camptothecin (CPT), a topoisomerase I inhibitor, which induces DSBs by blocking replication. Surprisingly, mammalian cells and chicken DT40 cells deficient in Rad18 display reduced HR-dependent repair and are hypersensitive to CPT. Deletion of nonhomologous end joining (NHEJ), a major DSB repair pathway in vertebrates, in rad18-deficient DT40 cells completely restored HR-mediated DSB repair, suggesting that vertebrate Rad18 regulates the balance between NHEJ and HR. We previously reported that loss of NHEJ normalized the CPT sensitivity of cells deficient in poly(ADP-ribose) polymerase 1 (PARP1). Concomitant deletion of Rad18 and PARP1 synergistically increased CPT sensitivity, and additional inactivation of NHEJ normalized this hypersensitivity, indicating their parallel actions. In conclusion, higher-eukaryotic cells separately employ PARP1 and Rad18 to suppress the toxic effects of NHEJ during the HR reaction at stalled replication forks.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Saberi A,Hochegger H,Szuts D,Lan L,Yasui A,Sale JE,Taniguchi Y,Murakawa Y,Zeng W,Yokomori K,Helleday T,Teraoka H,Arakawa H,Buerstedde JM,Takeda Sdoi
10.1128/MCB.01243-06subject
Has Abstractpub_date
2007-04-01 00:00:00pages
2562-71issue
7eissn
0270-7306issn
1098-5549pii
MCB.01243-06journal_volume
27pub_type
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