It has been long assumed that normally leading strand synthesis must proceed coordinated with the lagging strand to prevent strand uncoupling and the pathological accumulation of single-stranded DNA (ssDNA) in the cell, a dogma recently challenged by in vitro studies in prokaryotes. Here, we report that human DNA polymerases can function independently at each strand in vivo and that the resulting strand uncoupling is supported physiologically by a cellular tolerance to ssDNA. Active forks rapidly accumulate ssDNA at the lagging strand when POLA1 is inhibited without triggering a stress response, despite ssDNA formation being considered a hallmark of replication stress. Acute POLA1 inhibition causes a lethal RPA exhaustion, but cells can duplicate their DNA with limited POLA1 activity and exacerbated strand uncoupling as long as RPA molecules suffice to protect the elevated ssDNA. Although robust, this uncoupled mode of DNA replication is also an in-built weakness that can be targeted for cancer treatment.
Physiological Tolerance to ssDNA Enables Strand Uncoupling during DNA Replication / A. Ercilla, J. Benada, S. Amitash, G. Zonderland, G. Baldi, K. Somyajit, F. Ochs, V. Costanzo, J. Lukas, L. Toledo. - In: CELL REPORTS. - ISSN 2211-1247. - 30:7(2020), pp. 2416-2429.
|Titolo:||Physiological Tolerance to ssDNA Enables Strand Uncoupling during DNA Replication|
|Parole Chiave:||ATR; CD437; DNA replication; lagging strand; POLA1; polymerase alpha; replication catastrophe; RPA; ssDNA; strand uncoupling|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Progetto:||The role of essential DNA metabolism genes in vertebrate chromosome replication (DNAMEREP)|
|Data di pubblicazione:||2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.celrep.2020.01.067|
|Appare nelle tipologie:||01 - Articolo su periodico|