TopBP1 interacts with BLM to maintain genome stability but is dispensable for preventing BLM degradation

Molecular Cell
Andrew N BlackfordWojciech Niedzwiedz

Abstract

The Bloom syndrome helicase BLM and topoisomerase-IIβ-binding protein 1 (TopBP1) are key regulators of genome stability. It was recently proposed that BLM phosphorylation on Ser338 mediates its interaction with TopBP1, to protect BLM from ubiquitylation and degradation (Wang et al., 2013). Here, we show that the BLM-TopBP1 interaction does not involve Ser338 but instead requires BLM phosphorylation on Ser304. Furthermore, we establish that disrupting this interaction does not markedly affect BLM stability. However, BLM-TopBP1 binding is important for maintaining genome integrity, because in its absence cells display increased sister chromatid exchanges, replication origin firing and chromosomal aberrations. Therefore, the BLM-TopBP1 interaction maintains genome stability not by controlling BLM protein levels, but via another as-yet undetermined mechanism. Finally, we identify critical residues that mediate interactions between TopBP1 and MDC1, and between BLM and TOP3A/RMI1/RMI2. Taken together, our findings provide molecular insights into a key tumor suppressor and genome stability network.

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Citations

Jan 26, 2016·Nature Cell Biology·Ronan BroderickWojciech Niedzwiedz
Oct 13, 2015·Molecular Cell·Paul WijnhovenStephen P Jackson
Aug 13, 2015·Cell Cycle·Ronan Broderick, Wojciech Niedzwiedz
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Sep 4, 2016·Biochemical and Biophysical Research Communications·Seung Ho Choi, Hae Yong Yoo
Oct 28, 2016·Nature Cell Biology·Thomas E BassDavid Cortez
Oct 19, 2017·The Journal of Cell Biology·Emily Yun-Chia ChangPeter C Stirling
Nov 24, 2017·Cold Spring Harbor Symposia on Quantitative Biology·Kata SarlósIan D Hickson
Jan 9, 2020·Nature Communications·Clémence MooserManuel Stucki
Jan 28, 2021·Nature Communications·Ann-Marie K ShorrocksAndrew N Blackford
Oct 6, 2017·Structure·Georges Mer, Maria Victoria Botuyan
Mar 30, 2021·Frontiers in Genetics·Ekjot KaurSagar Sengupta
Sep 12, 2020·Seminars in Cell & Developmental Biology·Jonas BaggeMichael Lisby
Jul 23, 2021·Current Opinion in Genetics & Development·Aurore SanchezPetr Cejka

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Methods Mentioned

BETA
chromosomal aberrations
Transfections
immunoprecipitations
Pull-downs
pull-down

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