5exr
From Proteopedia
Crystal structure of human primosome
Structural highlights
Function[DPOA2_HUMAN] May play an essential role at the early stage of chromosomal DNA replication by coupling the polymerase alpha/primase complex to the cellular replication machinery (By similarity). [PRI1_HUMAN] DNA primase is the polymerase that synthesizes small RNA primers for the Okazaki fragments made during discontinuous DNA replication. [DPOLA_HUMAN] Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes.[1] [PRI2_HUMAN] DNA primase is the polymerase that synthesizes small RNA primers for the Okazaki fragments made during discontinuous DNA replication. Publication Abstract from PubMedThe human primosome, a 340 kilodalton complex of primase and DNA polymerase alpha (Pol alpha), synthesizes chimeric RNA-DNA primers to be extended by replicative DNA polymerases delta and . The intricate mechanism of concerted primer synthesis by two catalytic centers was an enigma for over three decades. Here we report the crystal structures of two key complexes, the human primosome and the C-terminal domain of the primase large subunit (p58C) with bound DNA/RNA duplex. These structures, along with analysis of primase/polymerase activities, provide a plausible mechanism for all transactions of the primosome including initiation, elongation, accurate counting of RNA primer length, primer transfer to Pol alpha, and concerted autoregulation of alternate activation/inhibition of the catalytic centers. Our findings reveal a central role of p58C in the coordinated actions of two catalytic domains in the primosome and ultimately could impact the design of anticancer drugs. MECHANISM OF CONCERTED RNA-DNA PRIMER SYNTHESIS BY THE HUMAN PRIMOSOME.,Baranovskiy AG, Babayeva ND, Zhang Y, Gu J, Suwa Y, Pavlov YI, Tahirov TH J Biol Chem. 2016 Mar 14. pii: jbc.M116.717405. PMID:26975377[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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