DNA Polymerase beta Accelerates Cellular DNA Base Excision Repair by Suppressing Excessive PARP1 Engagement

Abstract

DNA polymerase beta (POL{beta}) is required for rapid rates of cellular DNA base excision repair (BER). However, the reason for this requirement is unclear, because other DNA polymerases can replace POL{beta}, in vitro. Here, we have identified the essential role of POL{beta} during cellular BER. As expected, POL{beta} deletion in human RPE-1 cells resulted in the rapid accumulation of DNA strand break intermediates during incubation with the monofunctional alkylating agent, methyl methanesulphonate (MMS). However, this accumulation was not detected in cells that also lack PARP1, indicating that POL{beta} is required for BER only if PARP1 is present. This result is reminiscent of the essential role of XRCC1 during BER, which is to suppress the excessive engagement and activity of PARP1 at BER intermediates and thereby enable their access and repair by other enzymes. Indeed, we found that POL{beta} is required to prevent excessive PARP1 engagement and activity during BER, and that XRCC1 and POL{beta} fulfil this function together. Finally, similar to XRCC1, loss of POL{beta} leads to persistent transcriptional suppression during MMS-induced BER, and this suppression is alleviated by treatment with PARP inhibitor. In summary, we show here that the essential role of POL{beta} during cellular BER is to suppress excessive PARP1 engagement and activity, and thereby maintain rapid rates of this important DNA repair process.