Dr. Ivan Matic

Research Area: ADP-Ribosylation in the DNA Damage Response and Ageing

Branches: BiochemistryCancer BiologyCell Biology

Website: Matic Lab
Twitter: @Lab_Matic

1. Research Background:

A vital factor in comprehending ageing and age-related diseases involves understanding the signalingpathways operating within cells, which dictate crucial fate decisions. Key among these pathways, beginning with the DNA damage response, is the regulation by a post-translational modification known as ADP-ribosylation (ADPr). This modification is biologically and clinically significant, particularly renowned for its crucial role in maintaining genome stability. The overarching aim of our research group is to delve into the molecular mechanisms of DNA repair and ageing, especially elucidating the role of ADPr in these biological processes. Our group's seminal discoveries, including the identification of Serine ADPr by the HPF1/PARP1 writer complex as a novel type of histone mark (as detailed in our publications in Nature Chem Biol 2016, Mol Cell 2017, eLife 2018, and Cell Reports 2018), have paved the way for a burgeoning research area. This novel field seeks to shed light on how ADPr regulates the DNA damage response and chromatin dynamics. More recently, in a manner akin to the transformation of CRISPR/Cas9 into a powerful genome editing tool, we've leveraged our fundamental biological discoveries of Serine ADPr signaling to develop a cutting-edge chemical biology and modular antibody technology (Cell 2020, Mol Cell 2023, Nat Rev Mol Cell Biol. 2023, and Trends Biochem Sci. 2023). This places our laboratory at the forefront of research into the roles of mono-ADPr in ageing and has allowed us to reveal DNA damage- induced mono-ADP-ribosylation as a second wave of PARP1 signaling (Mol Cell 2023).

2. Research questions addressed by the group:

Future breakthroughs in ageing research, from basic biology to clinical applications, hinge on the deciphering of precise molecular mechanisms governing the multitude of biological pathways implicated in ageing and age-related diseases. Yet, elucidating the biochemical basis of specific biological processes often presents substantial challenges. Our ambition is to drive transformative fundamental discoveries that illuminate the enigmatic molecular mechanisms of ageing by applying advanced proteomics and innovative biochemical approaches.

Our first main direction currently is to establish the concept of histone mono-ADPr being a critical cellular signal that helps shape chromatin structure and regulates the recruitment of factors to DNA damage sites.

Secondly, our recent discoveries of RNF114 and other ubiquitin E3 ligases as readers of Serine mono-ADPr (Mol Cell 2023) suggest an extensive interplay between mono-ADPr and ubiquitination. These findings have spurred us to delve deeper into the crosstalk between these two protein modifications during the DNA damage response.

A third significant avenue for future research involves the investigation of SIRT6, a mono-ADP-ribosyl transferase implicated in multiple biological pathways related to ageing regulation. Despite being SIRT6's first identified enzymatic activity, its mono- ADPr activity received less attention than deacylation, largely due to a lack of reliable antibodies for mono-ADPr detection. We anticipate that application of our chemical biology/modular antibody technology (Cell 2020; Mol Cell 2023) will underscore the significance of SIRT6's mono-ADPr activity in ageing.

3. Possible project(s):

  1. Functional and mechanistic characterization of histone Ser-mono-ADP- ribosylation marks (H1, H2B, H3 andH4): identification and characterization of the readers of histone mono- ADP-ribosylation
  2. Interplay between mono-ADPr and ubiquitination signaling
  3. ADP-ribosylation in ageing: molecular mechanisms of the mono-ADP-ribosyl transferase activity of SIRT6

4. Applied Methods and model organisms:

  • Methods: advanced proteomics, computational data analyses, chemical biology approaches, biochemical purification, cell culture, western blotting, live-cell imaging, immunofluorescence, cell culture.
  • Model organisms: mammalian cell culture and the model organism African killifish.

5. Desirable skills and qualifications:

Ability to join an interdisciplinary, collaborative, and highly productive research environment, demonstratingflexibility to thrive in a rapidly advancing research field. The selected candidate will receive extensive training under thedirect supervision of the group leader, gaining proficiency in a variety of highly sought-after advanced technologies. Such experience will significantly enhance their career prospects within academia and beyond.

6. References and key publications:

  • Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling
    Longarini, E. J., Dauben, H., Locatelli, C., Wondisford, A. R., Smith, R., Muench, C., Kolvenbach, A., Lynskey,M. L., Pope, A., Bonfiglio, J. J., Jurado, E. P., Fajka-Boja, R., Colby, T., Schuller, M.,Ahel, I., Timinszky, G., O’Sullivan, R. J., Huet, S., Matic, I.
    (2023) Molecular Cell, published online: April 27, 2023
  • An HPF1/PARP1-Based Chemical Biology Strategy for Exploring ADP-Ribosylation
    Bonfiglio, J. J.Leidecker, O.Dauben, H.Longarini, E. J.Colby, T. San Segundo-Acosta, P.Perez, K. A. Matic, I.
    (2020) Cell, 183, 4, 1086-1102 e23
  • Interplay of Histone Marks with Serine ADP-Ribosylation
    Bartlett, E. Bonfiglio, J. J. Prokhorova, E. Colby, T. Zobel, F. Ahel, I. Matic, I.
    (2018) Cell Reports, 24(13):3488-3502.e5
  • Serine ADP-Ribosylation Depends on HPF1
    Bonfiglio, J. J. Fontana, P.Zhang, Q. Colby, T. Gibbs-Seymour, I. Atanassov, I.Bartlett, E.Zaja, R. Ahel, I. Matic, I.
    (2017) Molecular Cell, 65, 5, 932-940 e6
  • Serine is a new target residue for endogenous ADP-ribosylation on histones
    Leidecker, O. Bonfiglio, J. J. Colby, T.Zhang, Q.Atanassov, I.Zaja, R.Palazzo, L.Stockum, A.Ahel, I.Matic, I.
    (2016) Nature Chemical Biology, 12, 12, 998-1000