Sobeck Lab Website (currently under construction)
The stability of our 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 those genes encoding caretaker proteins cause genomic instability syndromes such as Fanconi Anemia or Bloom syndrome, characterized by an elevated risk to develop certain types of cancer. We study these diseases to understand and discover novel mechanisms important to suppress cancer susceptibility.
The Sobeck laboratory is particularly interested in the evolutionarily new Fanconi anemia (FA) pathway and its roles in genome maintenance. In the canonical FA pathway (Fig. 1A), an FA core complex (blue) is activated by DNA interstrand crosslinks (ICLs) in S-phase and monoubiquitinates the central FA pathway protein, FANCD2. FANCD2Ub then recruits downstream proteins to promote DNA ICL removal by homologous recombination (HR) repair.
We previously demonstrated that the non-ubiquitinated FANCD2 isoform acts independently of the FA core complex to promote the HR-dependent restart of temporarily stalled replication forks (Fig. 1B), in concert with other FA proteins such as FANCD2/BRCA2 (Breast Cancer Associated 2) and FANCJ/PALB2 (Partner And Localizer of BRCA2). We are now deciphering underlying molecular mechanisms of FA pathway-mediated replication recovery.
Excitingly, recent findings suggest that the FA pathway is functionally intertwined with other DNA repair factors (such as MRE11, CtIP) as well as chromatin remodeling/histone chaperone factors (such as the ATRX/DAXX histone H3.3 chaperone) to promote replication fork recovery.
Okamoto Y, Abe M, Mu A, Tempaku Y, Rogers CB, Mochizuki AL, Katsuki Y, Kanemaki MT, Takaori-Kondo A, Sobeck A, Bielinsky AK, Takata M (2021) SLFN11 promotes stalled fork degradation that underlies the phenotype in Fanconi anemia cells. Blood 137:336-348.
Raghunandan M, Yeo JE, Walter R, Saito K, Harvey AJ, Ittershagen S, Lee EA, Yang J, Hoatlin ME, Bielinsky AK, Hendrickson EA, Schärer O, Sobeck A (2020): Functional cross talk between the Fanconi anemia and ATRX/DAXX histone chaperone pathways promotes replication fork recovery. Hum Mol Genet 29:1083-1095.
Paulson CN, John K, Baxley RM, Kurniawan F, Orellana K, Francis R, Sobeck A, Eichman BF, Chazin WJ, Aihara H, Georg GI, Hawkinson JE, Bielinsky AK. Open Biol (2019) The anti-parasitic agent suramin and several of its analogues are inhibitors of the DNA binding protein Mcm10. Open Biol 9:190117.
Thompson EL, Yeo JE, Lee EA, Kan Y, Raghunandan M, Wiek C, Hanenberg H, Schärer OD, Hendrickson EA, Sobeck A (2017): FANCI and FANCD2 have common as well as independent functions during the cellular replication stress response. Nucleic Acids Res 45:11837-11857.
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