Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: Mechanistic insights

Larry H. Thompson, John M. Hinz

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

The Fanconi anemia (FA) molecular network consists of 15 "FANC" proteins, of which 13 are associated with mutations in patients with this cancer-prone chromosome instability disorder. Whereas historically the common phenotype associated with FA mutations is marked sensitivity to DNA interstrand crosslinking agents, the literature supports a more global role for FANC proteins in coping with diverse stresses encountered by replicative polymerases. We have attempted to reconcile and integrate numerous observations into a model in which FANC proteins coordinate the following physiological events during DNA crosslink repair: (a) activating a FANCM-ATR-dependent S-phase checkpoint, (b) mediating enzymatic replication-fork breakage and crosslink unhooking, (c) filling the resulting gap by translesion synthesis (TLS) by error-prone polymerase(s), and (d) restoring the resulting one-ended double-strand break by homologous recombination repair (HRR). The FANC core subcomplex (FANCA, B, C, E, F, G, L, FAAP100) promotes TLS for both crosslink and non-crosslink damage such as spontaneous oxidative base damage, UV-C photoproducts, and alkylated bases. TLS likely helps prevent stalled replication forks from breaking, thereby maintaining chromosome continuity. Diverse DNA damages and replication inhibitors result in monoubiquitination of the FANCD2-FANCI complex by the FANCL ubiquitin ligase activity of the core subcomplex upon its recruitment to chromatin by the FANCM-FAAP24 heterodimeric translocase. We speculate that this translocase activity acts as the primary damage sensor and helps remodel blocked replication forks to facilitate checkpoint activation and repair. Monoubiquitination of FANCD2-FANCI is needed for promoting HRR, in which the FANCD1/BRCA2 and FANCN/PALB2 proteins act at an early step. We conclude that the core subcomplex is required for both TLS and HRR occurring separately for non-crosslink damages and for both events during crosslink repair. The FANCJ/BRIP1/BACH1 helicase functions in association with BRCA1 and may remove structural barriers to replication, such as guanine quadruplex structures, and/or assist in crosslink unhooking.

Original languageEnglish (US)
Pages (from-to)54-72
Number of pages19
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume668
Issue number1-2
DOIs
StatePublished - Jul 31 2009
Externally publishedYes

Fingerprint

Fanconi Anemia Complementation Group Proteins
Recombinational DNA Repair
DNA Repair
Fanconi Anemia
S Phase Cell Cycle Checkpoints
Chromosome Disorders
G-Quadruplexes
Chromosomal Instability
Mutation
Ligases
Ubiquitin
DNA Replication
DNA Damage
Chromatin
Chromosomes
Phenotype
DNA
Neoplasms
Proteins

Keywords

  • Chromosomal instability
  • Crosslink repair
  • DNA crosslinking
  • DNA replication forks
  • Homologous recombination repair
  • Mutagenesis
  • Translesion synthesis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this

Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair : Mechanistic insights. / Thompson, Larry H.; Hinz, John M.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 668, No. 1-2, 31.07.2009, p. 54-72.

Research output: Contribution to journalArticle

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