Sonia Franco Lab Research

Mission

The goal of our laboratory is to define the cellular pathways used by mammalian cells to maintain genomic integrity. Our work is focused on understanding how DNA double-strand breaks (DSB) are detected, signaled and repaired in mammalian cells.

Approach

Human aging and cancer are complex, often interrelated, phenotypes. Mouse genetics provides a powerful tool to evaluate the requirement for specific factors for organismal homeostasis with age and under conditions of stress. We are using a series of knock-out and transgenic mouse models to define the regulation of the DNA Damage Response (DDR) and the Nonhomologus End-Joining (NHEJ) pathway in the repair of DNA double-strand breaks in distinct cellular contexts.

Projects

1. Regulation of DSB repair by the ATM kinase

Individuals with Ataxia-Telangiectasia show features of progeria and increased cancer predisposition. We are using a mouse model that reproduces many of the features of the disease to investigate how the ATM-regulated network of factors prevents cellular senescence, premature aging and transformation in vivo.

2. Deciphering functions for histone H2AX and 53BP1 in the DNA Damage Response

We are investigating how histone H2AX and 53BP1 differentially promote repair via either error-free or error-prone pathways at PARP1-deficient chromatin. In addition, we are using the APCmin mouse model of colon cancer to determine their roles in tissue stem cell transformation.

3. Differential roles for PARP1 and PARP2 in DSB repair

Using mice deficient for PARP1 or PARP2, we are investigating how poly(ADP)ribosylation at sites of DNA DSBs interacts with other chromatin modifications to regulate foci formation, cell cycle checkpoint activation and repair, and how unrepaired DNA damage in the absence of PARP1 or PARP2 affects organismal health and lifespan

4. Functions of the macroPARPs in the DNA damage response

The macroPARPs PARP9, PARP14 and PARP15 are overexpressed in many cancers. We are using a knock-down approach in human and mouse cells to investigate specific roles in the regulation of cellular senescence and transformation.

Recent Publications

 

     Rybanska-Spaeder I, Reynolds T, Chou J, Prakash M, Jefferson T, Huso DL, Desiderio S, Franco S. 53BP1 is limiting for nonhomologous end-joining-mediated repair in ATM-deficient cells subjected to oncogenic stress or radiation. Mol Cancer Res 11:1223-34, 2013.

     Rybanska I, Ishaq O, Chou J, Prakash M, Bakhsheshian J, Huso DL, Franco S. PARP1 and DNA-PKcs synergize to suppress p53 mutation and telomere fusions during T lineage lymphomagenesis. Oncogene. doi:10.1038/onc.2012. 199, 2012.

     Orsburn B, Escudero B, Prakash M, Gesheva S, Liu G, Huso DL, Franco S. Differential requirement for H2AX and 53BP1 in organismal development and genome maintenance in the absence of PARP1. Mol. Cell. Biol. 30(10):, 2010.

     Schenten D*, Kracker S*, Esposito G*, Franco S., Klein U, Murphy MM, Alt FW, Rajewsky K. Pol zeta ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair and genomic stability. J. Exp. Med. 206:477-490, 2009.

     Li G, Alt FW, Cheng H-L, Brush JW, Goff PH, Murphy MM, Franco S., Zhang Y, Zha S. Lymphocyte –specific compensation for XLF/Cernunnos end-joining functions in V(D)J recombination. Mol. Cell, 205:1949-57, 2008.

     Takizawa M, Tolarova H, Li Z, Dubois W, Lim S, Callen E, Franco S., Mosaico M, Feigenbaum L, Alt FW, Nussenzweig A, Potter M, Casellas R. AID expression levels determine the extent of cMyc oncogenic translocations and the incidence of B cell tumor development. J. Exp. Med. 205:1949-57, 2008.

     Franco S., Murphy MM, Li G, Borjeson T, Boboila C, Alt FW. DNA-PKcs and Artemis are required for the end-joining phase of immunoglobulin class switch recombination. J. Exp. Med. 205:557-564, 2008.

     Jabara H, Chaudhuri J, Dutt S, Dedeoglu F, Weng Y, Murphy MM, Franco S., Alt FW, Manis J, Geha RS. B cell receptor crosslinking delays activation-induced cytidine deaminase induction and inhibits class switch recombination to IgE. J Clin All Immunol 121:191-196, 2008.

     Chaudhuri J, Basu U, Zarrin A, Yan C, Franco S., Perlot T, Vuong B, Wang J, Phan RT, Datta A, Manis JP, Alt FW. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Advances in Immunology. 94:157-214, 2007.

     Yan CT, Boboila C, Souza EK, Franco S., Hickernell T, Murphy M, Gumaste S, Geyer M, Zarrin AA, Manis JP, Rajewsky K, Alt FW. IgH class switching and translocations employ a robust non-classical end-joining pathway. Nature 449:478-82, 2007.

     Franco S., Alt FW, Manis JP. Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair 5:1030-1041, 2006.

     Franco S., Blasco MA, Siedlak SL, Harris PL, Moreira PI, Perry G, Smith MA. Telomeres and telomerase in Alzheimer’s disease: epiphenomena or a new focus for therapeutic strategy? Alzheimers Dement. 2:164-8, 2006.

     Morales J, Franco S., Murphy MM, Bassing CH, Mills KD, Adams MM, Manis JP, Rassidakis GZ, Alt FW, Carpenter PB. 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proc. Natl. Acad. Sci. USA. 103:3310-3315, 2006.

     Mostoslavsky R, Chua K, Lombard D, Pang W, Fischer M, Gellon L, Liu P, Mostoslavsky G, Franco S., Murphy M, Mills K, Patel P, Hsu JT, Hong AL, Ford E, Cheng H-L, Kennedy C, Nunuez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hursting S, Barret JC, Guarente L, Mulligan R, Demple B, Yancopoulos G, Alt FW. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell.124:315-329, 2006.

     Franco S., Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin A, Yan C, Tepsuporn S, Morales JC, Adams MM, Lou Z, Bassing CH, Manis JP, Chen J, Carpenter PB, Alt FW. Histone H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell. 21:200-214, 2006.

     Lou Z, Minter-Dykhouse K, Franco S., Gostissa M, Rivera MA, Celeste A, Manis J, van Deursen J, Nussenzweig A, Paull TT, Alt FW, Chen J. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol. Cell. 21:187-200, 2006.

     Franco S., Blasco MA, Siedlak SL, Harris PL, Moreira PI, Perry G, Smith MA. Telomeres and telomerase in Alzheimer’s disease: epiphenomena or a new focus for therapeutic strategy? Alzheimers Dement. 2:164, 2006.

     Lombard DB, Chua KF, Mostoslavsky R, Franco S., Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell. 120:497-512, 2005.

     Chua KF, Mostoslavsky R, Lombard DL, Pang WW, Saito S, Franco S., Kaushal D, Cheng H-L, Fischer MR, Stokes N, Murphy MM, Appella E, Alt FW. Mammalian SIRT1 limits replicative lifespan in response to chronic genotoxic stress. Cell Metabol. 2:67-76, 2005.

     Franco S., Canela A, Klatt P, Blasco MA. Effectors of mammalian telomere dysfunction: a comparative transcriptome analyis using mouse models. Carcinogenesis 26:1613-1626, 2005.

     Keefe D, Franco S., Liu L, Trimarchi J, Cao B, Weitzen S, Agarwal S, Blasco MA. Telomere length predicts embryo fragmentation after in vitro fertilization in women-Toward a telomere theory of reproductive aging in women. Am J Obst Gynecol. 192:1256-1260, 2005.

     Franco S., van de Vrugt HJ, Fernandez P, Aracil M, Arwert F, Blasco MA. Telomere dynamics in fancg-deficient mouse and human cells. Blood. 104:3927-3935, 2004.

     Ferron S*, Mira H*, Franco S.*, Cano-Jaimez M, Bellmunt E, Ramirez C, Farinas I, Blasco MA. Telomere shortening and chromosomall instability abrogates proliferation of adult but not embryonic neural stem cells. Development. 131:4059-4070, 2004.

     Liu L, Franco S., Spyropoulos B, Moens PB, Blasco MA, Keefe DL. Irregular telomeres impair meiotic synapsis and recombination in mice. Proc. Natl. Acad. Sci. USA 101:6496-6501, 2004.

     Villa A, Navarro-Galve B, Bueno C, Franco S., Blasco MA, Martinez-Serrano A. Long-term molecular and cellular stability of human neural stem cell lines. Exp. Cell Res. 294: 559-570, 2004.

     Poch, E., Carbonell P, Franco S., Díez-Juan A, Blasco MA, Andres V. Short telomeres protect from diet-induced atherosclerosis in apolipoprotein E-null mice. FASEB J. 18(2):418-420, 2004.

     Keefe DL, Franco S., Liu L, Trimarchi J, Blasco M, Weitzen S. Short telomeres in the chromosomes of spare eggs predict poor prognosis following in vitro fertilization/embryo transfer-towards a telomere theory of reproductive aging in women. Fertil. Steril. 80(S3):1, 2003.

     Maraval A, Franco S., Vialas C, Pratviel G, Blasco MA, Meunier B. Porphyrin-aminoquinoline conjugates as telomerase inhibitors. Org. Biomol. Chem. 1(6): 921 - 927, 2003.

     Franco S., Ozkaynak MF, Sandoval C, Tugal O, Jayabose S, Engelhardt, Moore MAS. Telomere dynamics in childhood leukemia and solid tumors: a follow-up study. Leukemia 17(2):401-410, 2003.

     Leri A*, Franco S.*, Zacheo A, Barlucchi L, Chimenti S, Limana F, Nadal-Ginard B, Kajstura J, Anversa P, Blasco MA. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure. EMBO J. 22(1):131-139, 2003.

     Espejel S*, Franco S.*, Sgura A*, Eguia R, Blasco MA. DNA-PKcs functionally interacts with telomerase in maintaining telomere length in the mouse. EMBO J. 21(22):6275-6287, 2002.

     Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann H, Zender L, Klempnauer J, Flemming P, Franco S., Blasco MA, Manns, MP, Rudolph, KL. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16(9):935-942, 2002.

     MacKenzie KL, Franco S., Naiyer AJ, May C, Sadelain M, Rafii S, Moore MAS. Multiple stages of malignant transformation of human endothelial cells modelled by co-expression of telomerase reverse transcriptase, SV-40 large T antigen and oncogenic N-ras. Oncogene 21(27):4200-4211, 2002.

     Franco S., Alsheimer M, Herrera E, Benavente, R. Blasco MA. Mammalian meiotic telomeres: composition and ultraestructure in telomerase deficient mice. European J. Cell Biol. 81:1-6, 2002.

     Espejel S, Franco S., Rodríguez-Perales S, Cigudosa JC, Blasco MA. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 21(9):2207-2219, 2002.

     Franco S., Segura I, Riese H, Blasco MA. Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres. Cancer Res. 62(2):552-9, 2002.