DNA and chromosome transactions safeguarding genome integrity

Genome integrity is maintained by a finely tuned network of processes that span from the onset of DNA replication to the faithful segregation of chromosomes. A core set of evolutionarily conserved replisome-associated factors orchestrate the interplay between DNA replication, recombination, and sister chromatid cohesion, ensuring that dividing cells inherit stable genomes. Mutations in these factors underlie various genetic disorders and predispose individuals to cancer. But how do cells achieve such extraordinary precision in duplicating and organizing their genomes while preserving integrity?

Our laboratory takes a comprehensive, systems-level approach to uncover how cells replicate DNA accurately, repair damage with minimal mutagenesis, and segregate sister chromatids with fidelity. We focus on three interrelated research themes:

1.    Mechanisms of DNA Damage Tolerance During Replication
How do cells tolerate DNA lesions encountered during replication? Which signaling pathways and molecular principles govern the choice between recombination-based versus mutagenic bypass mechanisms? We investigate the regulatory dynamics at the replisome and within chromatin to unravel how DNA damage tolerance is executed and controlled.

2.    Coupling of Cohesion and Repair during Replication. 
How is sister chromatid cohesion established during DNA replication, and how does this influence replication fork architecture, DNA repair, and transcriptional programs? We dissect the consequences of perturbing the cohesion machinery and explore how cohesion interfaces with broader aspects of genome function, including DNA repair.

3.    Roles of SMC Complexes in Chromosome Structure and Genome Surveillance
How do structural maintenance of chromosomes (SMC) proteins contribute to genome organization, DNA repair, and transcriptional control throughout the cell cycle? We investigate how these complexes influence the persistence of topological DNA structures, chromatid organization and gene expression, focusing on their genomic localization and dynamic behavior.

By integrating these lines of research, we aim to illuminate the fundamental principles that safeguard genome integrity—insights that hold broad relevance for understanding the molecular basis of human disease and for advancing therapeutic strategies in cancer.

Barnabas Szakal, Michele Giannattasio, Dana Branzei* (2024). SnapShot: Tolerating replication stress.
Mol Cell, 84(1): 182-182.e1. doi: 10.1016/j.molcel.2023.11.031.

Aki Nunomiya, Barnabas Szakal, Dana Branzei* (2024). SnapShot: DNA repair pathways.
Mol Cell, 84(1):180-180.e1. doi: 10.1016/j.molcel.2023.11.030.

Ivan Psakhye*, Ryotaro Kawasumi, Takuya Abe, Kouji Hirota and Dana Branzei* (2023). PCNA recruits cohesin loader Scc2/NIPBL to ensure sister chromatid cohesion.
Nat Struct Mol Biol, 30:1286-1294. doi: 10.1038/s41594-023-01064-x.

Chinnu Rose Joseph, Sabrina Dusi, Michele Giannattasio, and Dana Branzei* (2022). Rad51-mediated replication of damaged templates relies on monoSUMOylated DDK kinase.
Nat Commun 13(1):2480. doi: 10.1038/s41467-022-30215-9.

Valeria Dolce, Sabrina Dusi, Michele Giannattasio, Chinnu Rose Joseph, Marco Fumasoni and Dana Branzei* (2022). Parental histone deposition on the replicated strands promotes error-free DNA damage tolerance and regulates drug resistance.
Genes Dev 36:167-179, doi: 10.1101/gad.349207.121.

Ryotaro Kawasumi, Takuya Abe, Ivan Psakhye, Keiji Miyata, Kouji Hirota, and Dana Branzei^* (2021). Vertebrate CTF18 and DDX11 essential function in cohesion is bypassed by preventing WAPL-mediated cohesin release.
Genes Dev 35:1368-1382, doi: 10.1101/gad.348581.121.

Ivan Psakhye and Dana Branzei*(2021). SMC complexes are guarded by the SUMO protease Ulp2
against SUMO-chain-mediated turnover.
Cell Reports 36(5):109485.

Sumedha Agashe, Chinnu Rose Joseph, Teresa Anne Clarisse Reyes, Demis Menolfi, Michele Giannattasio, Anja Waizenegger, Barnabas Szakal and Dana Branzei* (2021). Smc5/6 functions with Sgs1-Top3-Rmi1 to complete chromosome replication at natural pause sites.
Nat Commun 12(1):2111, doi.org/10.1038/s41467-021-22217-w.

Anja Waizenegger, Madhusoodanan Urulangodi, Carl P. Lehmann, Teresa Anne Clarisse Reyes, Irene Saugar, Jose Antonio Tercero, Barnabas Szakal, and Dana Branzei* (2020). Mus81-Mms4 endonuclease is an Esc2-STUbL-Cullin8 mitotic substrate impacting on genome integrity.
Nat Commun 11:5746 https://doi.org/10.1038/s41467-020-19503-4.

Ivan Psakhye, Federica Castellucci and Dana Branzei* (2019). SUMO-chain-regulated proteasomal degradation timing exemplified in DNA replication initiation.
Mol Cell 76: 632-645.

Takuya Abe, Ryotaro Kawasumi, Michele Giannattasio, Sabrina Dusi, Yui Yoshimoto, Keiji Miyata, Koyuki Umemura, Kouji Hirota, and Dana Branzei* (2018). AND-1 fork protection function prevents fork resection and is essential for proliferation.
Nat Commun 9: 3091. doi: 10.1038/s41467-018-05586-7.

Takuya Abe, Masato Ooka, Ryotaro Kawasumi, Keiji Miyata, Minoru Takata, Kouji Hirota, and Dana Branzei* (2018). Warsaw Breakage Syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites. Proc Natl Acad Sci pii: 201803110. doi: 10.1073/pnas.1803110115.

Ryotaro Kawasumi, Takuya Abe*, Hiroshi Arakawa, Massimiliano Garre, Kouji Hirota, and Dana Branzei* (2017). ESCO1/2 roles in chromosome structure and interphase chromatin organization.
Genes Dev 31:2136-2150.

Demis Menolfi, Axel Delamarre, Armelle Lengronne, Philippe Pasero and Dana Branzei* (2015). Essential Roles of the Smc5/6 Complex in Replication through Natural Pausing Sites and Endogenous DNA Damage Tolerance.
Mol Cell 60: 835-846.

Madhusoodanan Urulangodi, Marek Sebesta, Demis Menolfi, Barnabas Szakal, Julie Sollier, Alexandra Sisakova, Lumir Krejci, and Dana Branzei* (2015). Local regulation of the Srs2 helicase by the SUMO-like domain protein Esc2 promotes recombination at sites of stalled replication.
Genes Dev 29: 2067-2080.

Marco Fumasoni, Katharina Zwicky, Fabio Vanoli, Massimo Lopes and Dana Branzei* (2015). Error-free DNA damage tolerance and sister chromatid proximity during DNA Replication rely on the Polalpha/Primase/Ctf4 Complex.
Mol Cell 57: 812-823.

Michele Giannattasio, Katharina Zwicky, Cindy Follonier, Marco Foiani, Massimo Lopes, and Dana Branzei* (2014). Visualization of recombination-mediated damage-bypass by template switching.
Nature Struct Mol Biol 21: 884-892.