PDIP46 (DNA polymerase δ interacting protein 46) is an activating factor for human DNA polymerase δ
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Xiaoxiao Wang1,*, Sufang Zhang1,*, Rong Zheng1, Fu Yue1, Szu Hua Sharon Lin1, Amal A. Rahmeh1, Ernest Y.C. Lee1, Zhongtao Zhang1 and Marietta Y.W.T. Lee1
1 Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA
* These authors have contributed equally to this work
Marietta Y.W.T. Lee, email:
Keywords: DNA polymerase δ, DNA replication, PDIP46, POLDIP3, SKAR
Received: November 23, 2015 Accepted: January 25, 2016 Published: January 27, 2016
PDIP46 (SKAR, POLDIP3) was discovered through its interaction with the p50 subunit of human DNA polymerase δ (Pol δ). Its functions in DNA replication are unknown. PDIP46 associates with Pol δ in cell extracts both by immunochemical and protein separation methods, as well as by ChIP analyses. PDIP46 also interacts with PCNA via multiple copies of a novel PCNA binding motif, the APIMs (AlkB homologue-2 PCNA-Interacting Motif). Sites for both p50 and PCNA binding were mapped to the N-terminal region containing the APIMs. Functional assays for the effects of PDIP46 on Pol δ activity on singly primed ssM13 DNA templates revealed that it is a novel and potent activator of Pol δ. The effects of PDIP46 on Pol δ in primer extension, strand displacement and synthesis through simple hairpin structures reveal a mechanism where PDIP46 facilitates Pol δ4 synthesis through regions of secondary structure on complex templates. In addition, evidence was obtained that PDIP46 is also capable of exerting its effects by a direct interaction with Pol δ, independent of PCNA. Mutation of the Pol δ and PCNA binding region resulted in a loss of PDIP46 functions. These studies support the view that PDIP46 is a novel accessory protein for Pol δ that is involved in cellular DNA replication. This raises the possibility that altered expression of PDIP46 or its mutation may affect Pol δ functions in vivo, and thereby be a nexus for altered genomic stability.
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