PMID- 32966795
OWN - NLM
STAT- MEDLINE
DCOM- 20210505
LR  - 20210505
IS  - 2211-1247 (Electronic)
VI  - 32
IP  - 12
DP  - 2020 Sep 22
TI  - Common Fragile Sites Are Characterized by Faulty Condensin Loading after 
      Replication Stress.
PG  - 108177
LID - S2211-1247(20)31166-9 [pii]
LID - 10.1016/j.celrep.2020.108177 [doi]
LID - 108177
AB  - Cells coordinate interphase-to-mitosis transition, but recurrent cytogenetic 
      lesions appear at common fragile sites (CFSs), termed CFS expression, in a 
      tissue-specific manner after replication stress, marking regions of instability 
      in cancer. Despite such a distinct defect, no model fully provides a molecular 
      explanation for CFSs. We show that CFSs are characterized by impaired chromatin 
      folding, manifesting as disrupted mitotic structures visible with molecular 
      fluorescence in situ hybridization (FISH) probes in the presence and absence of 
      replication stress. Chromosome condensation assays reveal that 
      compaction-resistant chromatin lesions persist at CFSs throughout the cell cycle 
      and mitosis. Cytogenetic and molecular lesions are marked by faulty condensin 
      loading at CFSs, a defect in condensin-I-mediated compaction, and are coincident 
      with mitotic DNA synthesis (MIDAS). This model suggests that, in conditions of 
      exogenous replication stress, aberrant condensin loading leads to molecular 
      defects and CFS expression, concomitantly providing an environment for MIDAS, 
      which, if not resolved, results in chromosome instability.
CI  - Copyright (c) 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Boteva, Lora
AU  - Boteva L
AD  - MRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh 
      EH4 2XU, UK.
FAU - Nozawa, Ryu-Suke
AU  - Nozawa RS
AD  - MRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh 
      EH4 2XU, UK.
FAU - Naughton, Catherine
AU  - Naughton C
AD  - MRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh 
      EH4 2XU, UK.
FAU - Samejima, Kumiko
AU  - Samejima K
AD  - Wellcome Centre for Cell Biology, The University of Edinburgh, Michael Swann 
      Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
FAU - Earnshaw, William C
AU  - Earnshaw WC
AD  - Wellcome Centre for Cell Biology, The University of Edinburgh, Michael Swann 
      Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
FAU - Gilbert, Nick
AU  - Gilbert N
AD  - MRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh 
      EH4 2XU, UK. Electronic address: nick.gilbert@ed.ac.uk.
LA  - eng
GR  - MC_UU_00007/13/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_12018/24/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Rep
JT  - Cell reports
JID - 101573691
RN  - 0 (Chromatin)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (condensin complexes)
RN  - 38966-21-1 (Aphidicolin)
RN  - 9007-49-2 (DNA)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
SB  - IM
MH  - Adenosine Triphosphatases/*metabolism
MH  - Aphidicolin/pharmacology
MH  - Chromatin/metabolism
MH  - *Chromosome Fragile Sites
MH  - DNA/biosynthesis
MH  - *DNA Replication/drug effects
MH  - DNA-Binding Proteins/*metabolism
MH  - Epithelial Cells/drug effects/metabolism
MH  - Female
MH  - G2 Phase/drug effects
MH  - HCT116 Cells
MH  - Humans
MH  - Male
MH  - Mitosis/drug effects
MH  - Models, Biological
MH  - Multiprotein Complexes/*metabolism
MH  - *Stress, Physiological/drug effects
PMC - PMC7511797
OTO - NOTNLM
OT  - chromatin
OT  - chromosome
OT  - common fragile sites
OT  - condensation
OT  - condensin
OT  - genome stability
OT  - replication
OT  - replication stress
COIS- Declaration of Interests The authors declare no competing interests.
EDAT- 2020/09/24 06:00
MHDA- 2021/05/06 06:00
PMCR- 2020/09/22
CRDT- 2020/09/23 20:05
PHST- 2020/05/11 00:00 [received]
PHST- 2020/07/22 00:00 [revised]
PHST- 2020/08/31 00:00 [accepted]
PHST- 2020/09/23 20:05 [entrez]
PHST- 2020/09/24 06:00 [pubmed]
PHST- 2021/05/06 06:00 [medline]
PHST- 2020/09/22 00:00 [pmc-release]
AID - S2211-1247(20)31166-9 [pii]
AID - 108177 [pii]
AID - 10.1016/j.celrep.2020.108177 [doi]
PST - ppublish
SO  - Cell Rep. 2020 Sep 22;32(12):108177. doi: 10.1016/j.celrep.2020.108177.