FANCA safeguards interphase and mitosis during hematopoiesis in vivo

Zahi Abdul-Sater, Donna Cerabona, Elizabeth Sierra Potchanant, Zejin Sun, Rikki Enzor, Ying He, Kent Robertson, W. Goebel, Grzegorz Nalepa

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in nonhematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry. Loss of FA signaling rendered cells hypersensitive to spindle chemotherapeutics and allowed escape from the chemotherapy-induced spindle assembly checkpoint. In support of these findings, direct comparison of DNA crosslinking and anti-mitotic chemotherapeutics in primary FANCA-/- cells revealed genomic instability originating through divergent cell cycle checkpoint aberrations. Our data indicate that FA/BRCA signaling functions as an in vivo gatekeeper of genomic integrity throughout interphase and mitosis, which may have implications for future targeted therapies in FA and FA-deficient cancers.

Original languageEnglish (US)
Pages (from-to)1031-1046
Number of pages16
JournalExperimental Hematology
Volume43
Issue number12
DOIs
StatePublished - 2015

Fingerprint

Genomic Instability
Interphase
Hematopoiesis
Mitosis
M Phase Cell Cycle Checkpoints
Fanconi Anemia
Housekeeping
Cell Cycle Checkpoints
DNA Repair
Cell Division
DNA Damage
Microscopy
Genome
Drug Therapy
DNA
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

Abdul-Sater, Z., Cerabona, D., Potchanant, E. S., Sun, Z., Enzor, R., He, Y., ... Nalepa, G. (2015). FANCA safeguards interphase and mitosis during hematopoiesis in vivo. Experimental Hematology, 43(12), 1031-1046. https://doi.org/10.1016/j.exphem.2015.08.013

FANCA safeguards interphase and mitosis during hematopoiesis in vivo. / Abdul-Sater, Zahi; Cerabona, Donna; Potchanant, Elizabeth Sierra; Sun, Zejin; Enzor, Rikki; He, Ying; Robertson, Kent; Goebel, W.; Nalepa, Grzegorz.

In: Experimental Hematology, Vol. 43, No. 12, 2015, p. 1031-1046.

Research output: Contribution to journalArticle

Abdul-Sater, Z, Cerabona, D, Potchanant, ES, Sun, Z, Enzor, R, He, Y, Robertson, K, Goebel, W & Nalepa, G 2015, 'FANCA safeguards interphase and mitosis during hematopoiesis in vivo', Experimental Hematology, vol. 43, no. 12, pp. 1031-1046. https://doi.org/10.1016/j.exphem.2015.08.013
Abdul-Sater Z, Cerabona D, Potchanant ES, Sun Z, Enzor R, He Y et al. FANCA safeguards interphase and mitosis during hematopoiesis in vivo. Experimental Hematology. 2015;43(12):1031-1046. https://doi.org/10.1016/j.exphem.2015.08.013
Abdul-Sater, Zahi ; Cerabona, Donna ; Potchanant, Elizabeth Sierra ; Sun, Zejin ; Enzor, Rikki ; He, Ying ; Robertson, Kent ; Goebel, W. ; Nalepa, Grzegorz. / FANCA safeguards interphase and mitosis during hematopoiesis in vivo. In: Experimental Hematology. 2015 ; Vol. 43, No. 12. pp. 1031-1046.
@article{89115758188d41d093d85cdd118e4eaa,
title = "FANCA safeguards interphase and mitosis during hematopoiesis in vivo",
abstract = "The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in nonhematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry. Loss of FA signaling rendered cells hypersensitive to spindle chemotherapeutics and allowed escape from the chemotherapy-induced spindle assembly checkpoint. In support of these findings, direct comparison of DNA crosslinking and anti-mitotic chemotherapeutics in primary FANCA-/- cells revealed genomic instability originating through divergent cell cycle checkpoint aberrations. Our data indicate that FA/BRCA signaling functions as an in vivo gatekeeper of genomic integrity throughout interphase and mitosis, which may have implications for future targeted therapies in FA and FA-deficient cancers.",
author = "Zahi Abdul-Sater and Donna Cerabona and Potchanant, {Elizabeth Sierra} and Zejin Sun and Rikki Enzor and Ying He and Kent Robertson and W. Goebel and Grzegorz Nalepa",
year = "2015",
doi = "10.1016/j.exphem.2015.08.013",
language = "English (US)",
volume = "43",
pages = "1031--1046",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "12",

}

TY - JOUR

T1 - FANCA safeguards interphase and mitosis during hematopoiesis in vivo

AU - Abdul-Sater, Zahi

AU - Cerabona, Donna

AU - Potchanant, Elizabeth Sierra

AU - Sun, Zejin

AU - Enzor, Rikki

AU - He, Ying

AU - Robertson, Kent

AU - Goebel, W.

AU - Nalepa, Grzegorz

PY - 2015

Y1 - 2015

N2 - The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in nonhematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry. Loss of FA signaling rendered cells hypersensitive to spindle chemotherapeutics and allowed escape from the chemotherapy-induced spindle assembly checkpoint. In support of these findings, direct comparison of DNA crosslinking and anti-mitotic chemotherapeutics in primary FANCA-/- cells revealed genomic instability originating through divergent cell cycle checkpoint aberrations. Our data indicate that FA/BRCA signaling functions as an in vivo gatekeeper of genomic integrity throughout interphase and mitosis, which may have implications for future targeted therapies in FA and FA-deficient cancers.

AB - The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in nonhematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry. Loss of FA signaling rendered cells hypersensitive to spindle chemotherapeutics and allowed escape from the chemotherapy-induced spindle assembly checkpoint. In support of these findings, direct comparison of DNA crosslinking and anti-mitotic chemotherapeutics in primary FANCA-/- cells revealed genomic instability originating through divergent cell cycle checkpoint aberrations. Our data indicate that FA/BRCA signaling functions as an in vivo gatekeeper of genomic integrity throughout interphase and mitosis, which may have implications for future targeted therapies in FA and FA-deficient cancers.

UR - http://www.scopus.com/inward/record.url?scp=84961391910&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961391910&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2015.08.013

DO - 10.1016/j.exphem.2015.08.013

M3 - Article

C2 - 26366677

AN - SCOPUS:84961391910

VL - 43

SP - 1031

EP - 1046

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 12

ER -