Basal Activity of a PARP1-NuA4 Complex Varies Dramatically across Cancer Cell Lines

• PARP1 activity varies strongly across cell lines independent of DNA strand breaks
• PARP1 exists in at least three biochemically distinct states
• Basal activity of a PARP1-NuA4 complex accounts for differences across cell lines
• NuA4 is required for high basal activity of PARP1

SummaryPoly(ADP-ribose) polymerases (PARPs) catalyze poly(ADP-ribose) addition onto proteins, an important posttranslational modification involved in transcription, DNA damage repair, and stem cell identity. Previous studies established the activation of PARP1 in response to DNA damage, but little is known about PARP1 regulation outside of DNA repair. We developed an assay for measuring PARP activity in cell lysates and found that the basal activity of PARP1 was highly variable across breast cancer cell lines, independent of DNA damage. Sucrose gradient fractionation demonstrated that PARP1 existed in at least three biochemically distinct states in both high- and low-activity lines. A discovered complex containing the NuA4 chromatin-remodeling complex and PARP1 was responsible for high basal PARP1 activity, and NuA4 subunits were required for this activity. These findings present a pathway for PARP1 activation and a direct link between PARP1 and chromatin remodeling outside of the DNA damage response.

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