Journal
LIFE SCIENCE ALLIANCE
Volume 6, Issue 12, Pages -Publisher
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.202302067
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This study investigates the impact of RB dysfunction on genome stability and whether this change can be exploited in RB-deficient cancer cells. The findings demonstrate that RB loss leads to high levels of PARylation, and inhibiting PARylation allows RB-deficient cells to progress to mitosis despite replication stress. These defects result in high levels of DNA damage and compromised cell viability. Therefore, drugs targeting PARP1 and PARP2 may have clinical relevance in the treatment of RB-deficient cancers.
The retinoblastoma tumor suppressor protein (RB) interacts physically and functionally with a number of epigenetic modifying enzymes to control transcriptional regulation, respond to replication stress, promote DNA damage response and repair, and regulate genome stability. To better understand how disruption of RB function impacts epigenetic regulation of genome stability and determine whether such changes represent exploitable weaknesses of RB-deficient cancer cells, we performed an imaging-based screen to identify epigenetic inhibitors that promote DNA damage and compromise the viability of RB-deficient cells. We found that loss of RB alone leads to high levels of replication-dependent poly-ADP ribosylation (PARylation) and that preventing PARylation by trapping PARP enzymes on chromatin enables RB-deficient cells to progress to mitosis with unresolved replication stress. These defects contribute to high levels of DNA damage and compromised cell viability. We demonstrate this sensitivity is conserved across a panel of drugs that target both PARP1 and PARP2 and can be suppressed by reexpression of the RB protein. Together, these data indicate that drugs that target PARP1 and PARP2 may be clinically relevant for RB-deficient cancers.
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