DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

Abstract:

:RNA synthesis and DNA replication cease after DNA damage. We studied RNA synthesis using an in situ run-on assay and found ribosomal RNA (rRNA) synthesis was inhibited 24 h after UV light, gamma radiation or DNA cross-linking by cisplatin in human cells. Cisplatin led to accumulation of cells in S phase. Inhibition of the DNA repair proteins DNA-dependent protein kinase (DNA-PK) or poly(ADP-ribose) polymerase 1 (PARP-1) prevented the DNA damage-induced block of rRNA synthesis. However, DNA-PK and PARP-1 inhibition did not prevent the cisplatin-induced arrest of cell cycle in S phase, nor did it induce de novo BrdU incorporation. Loss of DNA-PK function prevented activation of PARP-1 and its recruitment to chromatin in damaged cells, suggesting regulation of PARP-1 by DNA-PK within a pathway of DNA repair. From these results, we propose a sequential activation of DNA-PK and PARP-1 in cells arrested in S phase by DNA damage causes the interruption of rRNA synthesis after DNA damage.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Calkins AS,Iglehart JD,Lazaro JB

doi

10.1093/nar/gkt502

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

7378-86

issue

15

eissn

0305-1048

issn

1362-4962

pii

gkt502

journal_volume

41

pub_type

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