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A gatekeeping function of the replicative polymerase controls pathway choice in the resolution of lesion-stalled replisomes

Journal Article


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Abstract


  • © 2019 National Academy of Sciences. All rights reserved. DNA lesions stall the replisome and proper resolution of these obstructions is critical for genome stability. Replisomes can directly replicate past a lesion by error-prone translesion synthesis. Alternatively, replisomes can reprime DNA synthesis downstream of the lesion, creating a single-stranded DNA gap that is repaired primarily in an error-free, homology-directed manner. Here we demonstrate how structural changes within the Escherichia coli replisome determine the resolution pathway of lesion-stalled replisomes. This pathway selection is controlled by a dynamic interaction between the proofreading subunit of the replicative polymerase and the processivity clamp, which sets a kinetic barrier to restrict access of translesion synthesis (TLS) polymerases to the primer/template junction. Failure of TLS polymerases to overcome this barrier leads to repriming, which competes kinetically with TLS. Our results demonstrate that independent of its exonuclease activity, the proofreading subunit of the replisome acts as a gatekeeper and influences replication fidelity during the resolution of lesion-stalled replisomes.

Authors


  •   Chang, Seungwoo (external author)
  •   Naiman, Karel (external author)
  •   Thrall, Elizabeth (external author)
  •   Kath, James (external author)
  •   Jergic, Slobodan
  •   Dixon, Nicholas E.
  •   Fuchs, Robert (external author)
  •   Loparo, Joseph (external author)

Publication Date


  • 2019

Citation


  • Chang, S., Naiman, K., Thrall, E., Kath, J., Jergic, S., Dixon, N., Fuchs, R. & Loparo, J. (2019). A gatekeeping function of the replicative polymerase controls pathway choice in the resolution of lesion-stalled replisomes. Proceedings of the National Academy of Sciences of the United States of America, 116 (51), 25591-25601.

Scopus Eid


  • 2-s2.0-85076705872

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2085&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/1071

Number Of Pages


  • 10

Start Page


  • 25591

End Page


  • 25601

Volume


  • 116

Issue


  • 51

Place Of Publication


  • United States

Abstract


  • © 2019 National Academy of Sciences. All rights reserved. DNA lesions stall the replisome and proper resolution of these obstructions is critical for genome stability. Replisomes can directly replicate past a lesion by error-prone translesion synthesis. Alternatively, replisomes can reprime DNA synthesis downstream of the lesion, creating a single-stranded DNA gap that is repaired primarily in an error-free, homology-directed manner. Here we demonstrate how structural changes within the Escherichia coli replisome determine the resolution pathway of lesion-stalled replisomes. This pathway selection is controlled by a dynamic interaction between the proofreading subunit of the replicative polymerase and the processivity clamp, which sets a kinetic barrier to restrict access of translesion synthesis (TLS) polymerases to the primer/template junction. Failure of TLS polymerases to overcome this barrier leads to repriming, which competes kinetically with TLS. Our results demonstrate that independent of its exonuclease activity, the proofreading subunit of the replisome acts as a gatekeeper and influences replication fidelity during the resolution of lesion-stalled replisomes.

Authors


  •   Chang, Seungwoo (external author)
  •   Naiman, Karel (external author)
  •   Thrall, Elizabeth (external author)
  •   Kath, James (external author)
  •   Jergic, Slobodan
  •   Dixon, Nicholas E.
  •   Fuchs, Robert (external author)
  •   Loparo, Joseph (external author)

Publication Date


  • 2019

Citation


  • Chang, S., Naiman, K., Thrall, E., Kath, J., Jergic, S., Dixon, N., Fuchs, R. & Loparo, J. (2019). A gatekeeping function of the replicative polymerase controls pathway choice in the resolution of lesion-stalled replisomes. Proceedings of the National Academy of Sciences of the United States of America, 116 (51), 25591-25601.

Scopus Eid


  • 2-s2.0-85076705872

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2085&context=smhpapers1

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/1071

Number Of Pages


  • 10

Start Page


  • 25591

End Page


  • 25601

Volume


  • 116

Issue


  • 51

Place Of Publication


  • United States