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Molecular Mechanism of Human Cancer Susceptibility

Highly specialized and partially redundant mechanisms have evolved to maintain genomic stability. New evidence suggests that one of these mechanisms is defective in Fanconi anemia (FA), a genetic model for human host susceptibility to cancer. FA is a rare but devastating multi-gene disease thought to have an underlying defect in DNA interstrand crosslink repair.
Current models suggest that a trigger point for the FA pathway is the activation of a downstream protein, FANCD2. A set of functionally-interdependent FA "core complex" proteins is indispensable for the function of FANCD2. How the core complex proteins mediate the enigmatic downstream function of FANCD2 is unclear. Emerging evidence links FANCD2 to DNA repair proteins BRCA1 and BRCA2 (also known as FA protein FANCD1), and a role in the DNA damage response during S-phase.

We developed cell-free assays for FA proteins based on replicating extracts from Xenopus eggs to dissect the key functional events during S-phase. These extracts allow us to analyze FA protein function and post-translational modifications during ongoing DNA synthesis that is precisely synchronized and under natural cell cycle control. The regulated association of xFANCD2 and core complex proteins with chromatin in S-phase is providing us with a biochemical platform for elucidating FANCD2 and FA core complex protein molecular function during events in DNA replication and repair.

Our long-term goal is to obtain a mechanistic explanation for proteins in the FA pathway that we hope will lead to new approaches for targeted drug design in Fanconi anemia, as well as for cancer prevention and treatment.

Recent Publications:

1: Landais I, Sobeck A, Stone S, LaChapelle A, Hoatlin ME. A novel cell-free screen identifies a potent inhibitor of the Fanconi anemia pathway. Int J Cancer.
2009 Feb 15;124(4):783-92. PubMed PMID: 19048618.

2: Xu D, Guo R, Sobeck A, Bachrati CZ, Yang J, Enomoto T, Brown GW, Hoatlin ME, Hickson ID, Wang W. RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability. Genes Dev. 2008 Oct 15;22(20):2843-55.
PubMed PMID: 18923082; PubMed Central PMCID: PMC2569887.

3: Wang LC, Stone S, Hoatlin ME, Gautier J. Fanconi anemia proteins stabilize replication forks. DNA Repair (Amst). 2008 Dec 1;7(12):1973-81. Epub 2008 Sep 25.
PubMed PMID: 18786657; PubMed Central PMCID: PMC2596863.

4: Wilson JB, Yamamoto K, Marriott AS, Hussain S, Sung P, Hoatlin ME, Mathew CG, Takata M, Thompson LH, Kupfer GM, Jones NJ. FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. Oncogene. 2008 Jun 12;27(26):3641-52. Epub 2008 Jan 21. PubMed PMID: 18212739.

5: Stone S, Sobeck A, van Kogelenberg M, de Graaf B, Joenje H, Christian J, Hoatlin ME. Identification, developmental expression and regulation of the Xenopus ortholog of human FANCG/XRCC9. Genes Cells. 2007 Jul;12(7):841-51. PubMed
PMID: 17584296.

6: Sobeck A, Stone S, Hoatlin ME. DNA structure-induced recruitment and activation of the Fanconi anemia pathway protein FANCD2. Mol Cell Biol. 2007 Jun;27(12):4283-92. Epub 2007 Apr 9. PubMed PMID: 17420278; PubMed Central PMCID:
PMC1900049.

7: Ling C, Ishiai M, Ali AM, Medhurst AL, Neveling K, Kalb R, Yan Z, Xue Y, Oostra AB, Auerbach AD, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Takata M, Meetei AR, Wang W. FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J. 2007 Apr 18;26(8):2104-14.
Epub 2007 Mar 29. PubMed PMID: 17396147; PubMed Central PMCID: PMC1852792.

8: Sobeck A, Stone S, Costanzo V, de Graaf B, Reuter T, de Winter J, Wallisch M, Akkari Y, Olson S, Wang W, Joenje H, Christian JL, Lupardus PJ, Cimprich KA, Gautier J, Hoatlin ME. Fanconi anemia proteins are required to prevent accumulation of replication-associated DNA double-strand breaks. Mol Cell Biol.
2006 Jan;26(2):425-37. PubMed PMID: 16382135; PubMed Central PMCID: PMC1346898.

9: Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005 Sep;37(9):958-63. Epub 2005 Aug 21.
PubMed PMID: 16116422; PubMed Central PMCID: PMC2704909.

Related Links:

OHSU - The Hoatlin Lab

The Hoatlin Lab Wiki @ OpenWetWare

Dr. Hoatlin's PubMed Listing