Differential role of RB in response to UV and IR damage

Emily E. Bosco, Erik S. Knudsen

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The retinoblastoma tumor suppressor (RB) is functionally inactivated in the majority of cancers and is a critical mediator of DNA damage checkpoints. Despite the critical importance of RB function in tumor suppression, the coordinate impact of RB loss on the response to environmental and therapeutic sources of damage has remained largely unexplored. Here, we utilized a conditional knockout system to ablate RB in adult fibroblasts. This model system enabled us to investigate the temporal role of RB loss on cell cycle checkpoints and DNA damage repair following ultraviolet (UV) and ionizing radiation (IR) damage. We demonstrate that RB loss compromises rapid cell cycle arrest following UV and IR exposure in adult primary cells. Detailed kinetic analysis of the checkpoint response revealed that disruption of the checkpoint is concomitant with RB target gene deregulation, and is not simply a manifestation of chronic RB loss. RB loss had a differential effect upon repair of the major DNA lesions induced by IR and UV. Whereas RB did not affect resolution of DNA double-strand breaks, RB-deficient cells exhibited accelerated repair of pyrimidine pyrimidone photoproducts (6-4 PP). In parallel, this repair was coupled with enhanced expression of specific factors and the behavior of proliferating cell nuclear antigen (PCNA) recruitment to replication and repair foci. Thus, RB loss and target gene deregulation hastens the repair of specific lesions distinct from its ubiquitous role in checkpoint abrogation.

Original languageEnglish (US)
Pages (from-to)1581-1592
Number of pages12
JournalNucleic Acids Research
Volume33
Issue number5
DOIs
StatePublished - 2005

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Ionizing Radiation
Cell Cycle Checkpoints
DNA Repair
DNA Damage
Neoplasms
Double-Stranded DNA Breaks
Retinoblastoma
Proliferating Cell Nuclear Antigen
Genes
Fibroblasts
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Differential role of RB in response to UV and IR damage. / Bosco, Emily E.; Knudsen, Erik S.

In: Nucleic Acids Research, Vol. 33, No. 5, 2005, p. 1581-1592.

Research output: Contribution to journalArticle

Bosco, Emily E. ; Knudsen, Erik S. / Differential role of RB in response to UV and IR damage. In: Nucleic Acids Research. 2005 ; Vol. 33, No. 5. pp. 1581-1592.
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