Open Access

Letter to the editor for “Update of the human and mouse Fanconi anemia genes”

Human Genomics201610:25

https://doi.org/10.1186/s40246-016-0081-3

Received: 14 May 2016

Accepted: 14 June 2016

Published: 4 July 2016

After our review of the “Update of the human and mouse Fanconi anemia genes” had been published [1], a report appeared [2] that we believe contains additional important and clarifying information relevant to our discussion of the “Fanconi anemia pathway” and cross-talk with other DNA-repair pathways.

In Fig. 1, which is a modified version of the Figure 2 cartoon in our recent review [1], we had shown that, in response to upstream DNA damage signaling (such as phosphorylation by ATR/ATM) in the “FA/BRCA pathway,” the FA core complex comprises at least 11 proteins. These include FANCA (A), FANCB (B), FANCC (C), FANCE (E), FANCF (F), FANCG (G), FANCM (M), and FANCL (L) proteins, plus three FAAP proteins (FAAP20, FAAP24, and FAAP100). This core complex binds UBE2T (T) by way of FANCL; the resultant complex then activates FANCD2/I dimers by means of mono-ubiquitination, and we had written that this is an essential prerequisite for repairing DNA interstrand cross-links.
Fig. 1

The revised diagram

The activated FANCD2/I (D2/I) complex then translocates to DNA damage sites and recruits downstream FA effector proteins. These include BRCA1 (S), BRCA2 (D1), RAD51 (R), BRIP1 (J), PALB2 (N), RAD51C (O), SLX4 (P), and ERCC4 (Q), plus other DNA-repair molecules (including FA-associated nuclease-1 (FAN1)), as illustrated as the orange ellipse at the far right in our Fig. 1 diagram [1]. This large complex then migrates to the site of the lesion to repair the DNA damage.

It had been presumed that FAN1, also required for interstrand cross-link repair, is recruited by ubiquitinated FANCD2/I (light green ellipse in Fig. 1) [1]. However, Lachaud and coworkers, using FAN1 nuclease-deficient mice, recently demonstrated [2] that recruitment of FAN1 by ubiquitinated FANCD2/I is not essential for interstrand cross-link repair. As an alternative, FAN1 recruitment and activity restrain DNA replication fork progression. This restraint, in turn, holds in check any chromosomal abnormalities from occurring, when the DNA replication forks stall. And this pause can happen––even in the absence of interstrand cross-links.

Consequently, recruitment of FAN1 by ubiquitinated FANCD2 may be regarded as facilitating the processing of stalled forks during DNA replication. Although this checkpoint process is essential for genome stability and improved overall well-being of the cell, it might better be described as not absolutely necessary. Therefore, a slightly revised figure is proposed here, in which FAN1 can be either bound or not bound from the remainder of this complex (comprising D2/I, S, D1, R, J, N, O, P, Q, and other DNA repair molecules). This revised diagram now takes into account the latest data published by Lachaud et al. [2].

Future experiments using other knockout mice will clarify this pathway further. Given the recent advances with CRISPR/Cas9 methodology, knockout mouse lines––or cells in culture––can be efficiently created for all components shown in the figure herein, and then all permutations can be examined, one-by-one.

Declarations

Acknowledgements

This work was supported in part by the NIH Grants AA022057 and AA021724 (VV), U41HG003345 (EAB), P30 ES006096 (DWN), and the Wellcome Trust grant 099129/Z/12/Z (EAB).

Authors’ contributions

DWN drafted the manuscript. EAB, DCT, HJ, and VV edited the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Pediatrics and Molecular Developmental Biology, Division of Human Genetics, Children’s Hospital Medical Center
(2)
Department of Environmental Health and Center for Environmental Genetics, University Cincinnati Medical Center
(3)
Department of Environmental Health Sciences, Yale School of Public Health
(4)
HUGO Gene Nomenclature Committee (HGNC), European Bioinformatics Institute-European Molecular Biology Laboratory (EMBL-EBI)
(5)
Department of Clinical Practice, University of Colorado Denver
(6)
Department of Clinical Genetics and the Cancer Center, Amsterdam/VUmc Institute for Cancer and Immunology, VU University Medical Center

References

  1. Dong H, Nebert DW, Bruford EA, Thompson DC, Joenje H, Vasiliou V. Update of the human and mouse Fanconi anemia genes. Hum Genomics. 2015;9(1):32.View ArticlePubMedPubMed CentralGoogle Scholar
  2. Lachaud C, Moreno A, Marchesi F, Toth R, Blow JJ, Rouse J. Ubiquitinated FANCD2 recruits FAN1 to stalled replication forks to prevent genome instability. Science. 2016;351(6275):846–9.View ArticlePubMedGoogle Scholar

Copyright

© The Author(s). 2016

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