Publication: Human syndromes with genomic instability and multiprotein machines
that repair DNA double-strand breaks
Authors
De la Torre, C. ; Pincheira, J. ; Lopez-Saez, J.F.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
The present report deals with the functional
relationships among protein complexes which, when
mutated, are responsible for four human syndromes
displaying cancer proneness, and whose cells are
deficient in DNA double-strand break (DSB) repair. In
some of them, the cells are also unable to activate the
proper checkpoint, while in the others an unduly
override of the checkpoint-induced arrest occurs. As a
consequence, all these patients display genome
instability. In ataxia-telangiectasia, the mutated protein
(ATM) is a kinase, which acts as a transducer of DNA
damage signalling. The defective protein in the ataxiatelangiectasia-
like disorder is a DNase (the Mre11
nuclease) that in vivo produces single-strand tails at both
sides of DSBs. Mre11 is always present with the Rad50
ATPase in a protein machine: the nuclease complex. In
mammals, this complex also contains nibrin, the protein
mutated in the Nijmegen syndrome. Nibrin confers new
abilities to the nuclease complex, and can also bind to
BRCA1 (one of the two proteins mutated in familial
breast cancer). BRCA1 has a central motif that binds
with high affinity to cruciform DNA, a structure present
in places where the DNA loops are anchored to the
chromosomal axis or scaffold. The BRCA1•cruciform
DNA complex should be released to allow the nuclease
complex to work in DNA recombinational repair of DSBs. BRCA1 also acts as a scaffold for the assembly of
ATPases such as Rad51, responsible for the somatic
homologous recombination. Loss of the BRCA1 gene
prevents cell survival after exposure to cross-linkers.
The BRCA1-RING domain is an E3-ubiquitin ligase. It
can mono-ubiquitinate the FANCD2 protein, mutated in
one of the Fanconi anemia complementation groups, to
regulate it. Finally, during DNA replication, the nuclease complex and its activating ATM kinase are integrated in
the BRCA1-associated surveillance complex (BASC)
that contains, among others, enzymes required for
mismatch excision repair. In short, the proteins missing
in these syndromes have in common their BRCA1-
mediated assembly into multimeric machines
responsible for the surveillance of DNA replication,
DSB recombinational repair, and the removal of DNA
cross-links.
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