Repair of laser-localized DNA interstrand cross-links in G1 phase mammalian cells.
Interstrand cross-links (ICLs) are absolute blocks to transcription and replication and can provoke genomic instability and cell death. Studies in bacteria define a two-stage repair scheme, the first involving recognition and incision on either side of the cross-link on one strand (unhooking), followed by recombinational repair or lesion bypass synthesis. The resultant monoadduct is removed in a second stage by nucleotide excision repair. In mammalian cells, there are multiple, but poorly defined, pathways, with much current attention on repair in S phase. However, many questions remain, including the efficiency of repair in the absence of replication, the factors involved in cross-link recognition, and the timing and demarcation of the first and second repair cycles. We have followed the repair of laser-localized lesions formed by psoralen (cross-links/monoadducts) and angelicin (only monoadducts) in mammalian cells. Both were repaired in G(1) phase by nucleotide excision repair-dependent pathways. Removal of psoralen adducts was blocked in XPC-deficient cells but occurred with wild type kinetics in cells deficient in DDB2 protein (XPE). XPC protein was rapidly recruited to psoralen adducts. However, accumulation of DDB2 was slow and XPC-dependent. Inhibition of repair DNA synthesis did not interfere with DDB2 recruitment to angelicin but eliminated recruitment to psoralen. Our results demonstrate an efficient ICL repair pathway in G(1) phase cells dependent on XPC, with entry of DDB2 only after repair synthesis that completes the first repair cycle. DDB2 accumulation at sites of cross-link repair is a marker for the start of the second repair cycle.
Muniandy
Parameswary A
PA
Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Thapa
Dennis
D
Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224.
Thazhathveetil
Arun Kalliat
AK
Department of Chemistry, Northwestern University, Evanston, Illinois 60208.
Liu
Su-Ting
ST
BASF Company, 1 Connaught Place, Hong Kong.
Seidman
Michael M
MM
Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224. Electronic address: seidmanm@grc.nia.nih.gov.
D000818:Animals; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005363:Ficusin / Q000494:pharmacology; D011564:Furocoumarins / Q000494:pharmacology; D016193:G1 Phase / Q000235:genetics*; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D007834:Lasers; D015394:Molecular Structure
D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D011564:Furocoumarins; D007364:Intercalating Agents; C086984:XPC protein, human; D004247:DNA; C011659:angelicin; D005363:Ficusin
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