期刊
LIFE SCIENCE ALLIANCE
卷 2, 期 4, 页码 -出版社
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.201900321
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资金
- European Union [707299]
- Swiss National Science Foundation [PP00P3_144784/1, PP00P3_172959/1]
- Human Frontier Science Program [CDA00043/2013-C]
- Swiss National Science Foundation (SNF) [PP00P3_144784, PP00P3_172959] Funding Source: Swiss National Science Foundation (SNF)
- Marie Curie Actions (MSCA) [707299] Funding Source: Marie Curie Actions (MSCA)
Replication of eukaryotic genomes relies on the family B DNA polymerases Pol alpha, Pol delta, and Pol epsilon. All of these enzymes coordinate an iron-sulfur (FeS) cluster, but the function of this cofactor has remained largely unclear. Here, we show that the FeS cluster in the catalytic subunit of human Pol delta is coordinated by four invariant cysteines of the C-terminal CysB motif. FeS cluster loss causes a partial destabilisation of the four-subunit enzyme, a defect in double-stranded DNA binding, and compromised polymerase and exonuclease activities. Importantly, complex stability, DNA binding, and enzymatic activities are restored in the presence of proliferating cell nuclear antigen. We further show that also more subtle changes to the FeS cluster-binding pocket that do not abolish FeS cluster binding can have repercussions on the distant exonuclease domain and render the enzyme error-prone. Our data hence suggest that the FeS cluster in human Pol delta is an important co-factor that despite its C-terminal location has an impact on both DNA polymerase and exonuclease activities, and can influence the fidelity of DNA synthesis.
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