4.8 Article

A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol

期刊

NUCLEIC ACIDS RESEARCH
卷 49, 期 4, 页码 2179-2191

出版社

OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab049

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资金

  1. Knut and Alice Wallenberg Foundation
  2. Swedish Research Council
  3. JSPS Overseas Research Fellowship [201860287]
  4. Spanish Ministry of Economy and Competitiveness [BFU2015-65880-P, PGC2018-093576-B-C21]
  5. FPU-predoctoral fellowship from Spanish Ministry of Economy and Competitiveness
  6. Kempe Foundation
  7. Knut och Alice Wallenbergs Stiftelse

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PrimPol interacts with PolDIP2 to enhance its processivity, increasing primer-template and dNTP binding affinities, and thereby enhancing nucleotide incorporation efficiency. This mechanism, involving a unique arginine cluster in PolDIP2, may be critical for PrimPol's function in tolerating DNA lesions at physiological nucleotide concentrations.
Replication forks often stall at damaged DNA. To overcome these obstructions and complete the DNA duplication in a timely fashion, replication can be restarted downstream of the DNA lesion. In mammalian cells, this repriming of replication can be achieved through the activities of primase and polymerase PrimPol. PrimPol is stimulated in DNA synthesis through interaction with PolDIP2, however the exact mechanism of this PolDIP2-dependent stimulation is still unclear. Here, we show that PrimPol uses a flexible loop to interact with the C-terminal ApaG-like domain of PolDIP2, and that this contact is essential for PrimPol's enhanced processivity. PolDIP2 increases primer-template and dNTP binding affinities of PrimPol, which concomitantly enhances its nucleotide incorporation efficiency. This stimulation is dependent on a unique arginine cluster in PolDIP2. Since the polymerase activity of PrimPol alone is very limited, this mechanism, where the affinity for dNTPs gets increased by PolDIP2 binding, might be critical for the in vivo function of PrimPol in tolerating DNA lesions at physiological nucleotide concentrations.

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