TY - JOUR
T1 - Mechanism of Concerted RNA-DNA Primer Synthesis by the Human Primosome
AU - Baranovskiy, Andrey G.
AU - Babayeva, Nigar D.
AU - Zhang, Yinbo
AU - Gu, Jianyou
AU - Suwa, Yoshiaki
AU - Pavlov, Youri I.
AU - Tahirov, Tahir H.
N1 - Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Published.
PY - 2016/5/6
Y1 - 2016/5/6
N2 - The human primosome, a 340-kilodalton complex of primase and DNA polymeraseα(Polo α), synthesizes chimeric RNA-DNA primers to be extended by replicative DNA polymerases δand ϵ. 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 Polα, 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.
AB - The human primosome, a 340-kilodalton complex of primase and DNA polymeraseα(Polo α), synthesizes chimeric RNA-DNA primers to be extended by replicative DNA polymerases δand ϵ. 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 Polα, 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.
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U2 - 10.1074/jbc.M116.717405
DO - 10.1074/jbc.M116.717405
M3 - Article
C2 - 26975377
AN - SCOPUS:84966330175
SN - 0021-9258
VL - 291
SP - 10006
EP - 10020
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 19
ER -