The stability of the cellular genome is constantly threatened by exogenous and endogenous mutagenic agents such as UV light or reactive oxygen species. Cells protect their genome against carcinogenic alterations by using a complex network of “caretaker” proteins that function to maintain the integrity of the cellular chromosomes. Inherited defects in these caretaker genes are the cause of genomic instability syndromes in humans, such as Fanconi Anemia or Bloom syndrome, characterized by a highly elevated risk to develop certain types of cancer. We study these diseases to understand and discover novel mechanisms important to control and suppress cancer susceptibility.
Our lab is particularly interested in the evolutionarily new Fanconi anemia (FA) caretaker pathway.
According to the current FA pathway model, a large nuclear complex of at least ten FA proteins is required to activate two downstream target proteins, FANCD2 and FANCI, via monoubiquitination (see cartoon, Ub = Ubiquitin). This activation occurs in response to DNA damage but also during every S-phase of the cell cycle, when cells replicate their chromosomes. Thus, the FA pathway is suspected to have important functions to prevent DNA damage that occurs naturally during every round of chromosomal replication.
To identify the roles of FA proteins in the DNA damage response, we use human cells as well as egg extracts from the African clawed frog, Xenopus laevis. Xenopus is an extremely powerful cell free system that uniquely mirrors cellular replication of DNA complete with the assembly of chromatin into a functional nucleus.
The lab applies a combination of biochemistry, genetics, and imaging techniques to elucidate molecular mechanisms that underlie the FA caretaker functions, and to understand how FA proteins are networked with other caretaker proteins including the breast cancer-associated FA proteins BRCA1 (FANCS) and BRCA2 (FANCD1), as well as non-FA DNA repair factors such as the BLM helicase or CtIP.
For additional information, please click on the link to our external website above.
Castella M, Jacquemont C, Thompson EL, Yeo JE, Cheung RS, Huang JW, Sobeck A, Hendrickson EA, Taniguchi T (2015): FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2. PLoS Genet 11: e1005563.
Budzowska M, Graham TG, Sobeck A, Waga S, Walter JC (2015): Regulation of the Rev1-pol ζ complex during bypass of a DNA interstrand cross-link. EMBO J 34: 1971-85.
Raghunandan M, Chaudhury I, Kelich SL, Hanenberg H, Sobeck A (2015): FANCD2, FANCJ and BRCA2 cooperate to promote replication fork recovery independently of the Fanconi Anemia core complex. Cell Cycle 14: 342-53.
Chaudhury I, Stroik DR, Sobeck A (2014): FANCD2-controlled chromatin access of the Fanconi-associated nuclease FAN1 is crucial for the recovery of stalled replication forks. Mol Cell Biol 34: 3939-54.
Yeo JE, Lee EH, Hendrickson EA, Sobeck A (2014): CtIP mediates replication fork recovery in a FANCD2-regulated manner. Hum Mol Genet 23: 3695-705.
Chaudhury I, Sareen A, Raghunandan M, Sobeck A (2013): FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery. Nucleic Acids Res 41: 6444-59.
Sareen A, Chaudhury I, Adams N, Sobeck A (2012): Fanconi anemia proteins FANCD2 and FANCI exhibit different DNA damage responses during S-phase. Nucleic Acids Res 40: 8425-39.
Landais I*, Sobeck A*, Stone S*, LaChapelle A, Hoatlin M (2009): A novel cell-free screen identifies a potent inhibitor of the Fanconi Anemia pathway. Int. J. Cancer (Cover) 124: 783-92.
* Equal Contribution