During every S-phase cells need to duplicate their genomes so that both
daughter cells inherit complete copies of genetic information. It is a tremendous task,
given the large sizes of mammalian genomes and the required precision of DNA
replication. A major threat to the accuracy and efficiency of DNA synthesis is the
presence of damaged DNA, e.g. abasic sites, single stranded DNA breaks, DNA
crosslinks and adducts. This damage can be caused by exogenous age

Budzowska, M. (Magdalena)

Budzowska, M (Magdalena)

EUR Research Repository

English

Cellular responses to replication problems

During every S-phase cells need to duplicate their genomes so that both
daughter cells inherit complete copies of genetic information. It is a tremendous task,
given the large sizes of mammalian genomes and the required precision of DNA
replication. A major threat to the accuracy and efficiency of DNA synthesis is the
presence of damaged DNA, e.g. abasic sites, single stranded DNA breaks, DNA
crosslinks and adducts. This damage can be caused by exogenous agents, e.g.
UV light, ionizing radiation, or environmental carcinogens, but is also an inevitable
consequence of normal cellular metabolism. Replicative DNA polymerases, which
carry out the bulk of DNA synthesis, evolved to do their job extremely precisely
and effficiently. However, they are unable to use damaged DNA as templates, and,
consequently, are stopped at most DNA lesions. Failure to restart such stalled forks
can result in major chromosomal aberrations and lead to cell dysfunction or death.
Therefore, a well-coordinated response to replication perturbation is essential for cell
survival and wellbeing. It involves adjusting cell cycle progression to the emergency
situation, and the use of specialized pathways promoting replication recovery. The
aim of this thesis was to contribute to our understanding of the mechanisms the cell
employs to deal with replication problems

Erasmus University Digital Repository

Stellingenbehorende bij het proefschriftCellular responses to replication problemsMagdalena Budzowska1. Rad17 and the 9-1-1 complex not only participate in checkpoint signaling, but are likely to be directly involved in DNA replication, damage repair, and/or damage bypass. This thesis, Chapter 12. Mus81-Eme1 structure specifi c endonuclease is involved in processing recombination intermediates generated at stalled replication forks. Hanada et al., Nat Struct Mol Biol. 2007; this thesis, Chapter 53. Detection of low levels of DSBs formed in vivo is diffi cult, since both the use of gamma-H2AX antibodies and PFGE technique have serious limitations. Hanada et al., EMBO J. 2006, this thesis, Chapter 44. A lot of attention is focused on RAD51, the catalytic core of homologous recombination. However, the proteins that regulate RAD51 are the key to understanding how recombination reactions are controlled.Modesti et al., Mol Cell. 2007, this thesis, Chapter 65. Damaged DNA and active replication forks present below a threshold level in the G2 phase might fail to activate checkpoint signaling.Torres-Rosell et al., Science 2007, this thesis, Chapter 56. Restart of the cell cycle following a DNA damage checkpoint arrest is not a default pathway, but requires active signaling.Freire et al., Cell Cycle 20067. It is evident that individuals differ in the ability to repair DNA; however, with the current techniques, it is impossible to measure absolute or relative DNA repair capacity.8. Genomic instability can turn out to be not just the driving force but also the Achil-les’ heel of cancer.Murga and Fernández-Capetillo, Clin Transl Oncol 20079. Translesion synthesis and homologous recombination are likely to be more closely interconnected that generally appreciated.10. Doubt grows with knowledge. Johann Wolfgang von Goethe11. Very little is needed to make a happy life, it is all within yourself, in your way of thinking.Marcus Aurelius26th March 2008Stellingen.indd   1 2/24/08   5:10:43 PMStellingenbehorende bij het proefschriftCellular responses to replication problemsMagdalena Budzowska1. Rad17 and the 9-1-1 complex not only participate in checkpoint signaling, but are likely to be directly involved in DNA replication, damage repair, and/or damage bypass. This thesis, Chapter 12. Mus81-Eme1 structure specifi c endonuclease is involved in processing recombination intermediates generated at stalled replication forks. Hanada et al., Nat Struct Mol Biol. 2007; this thesis, Chapter 53. Detection of low levels of DSBs formed in vivo is diffi cult, since both the use of gamma-H2AX antibodies and PFGE technique have serious limitations. Hanada et al., EMBO J. 2006, this thesis, Chapter 44. A lot of attention is focused on RAD51, the catalytic core of homologous recombination. However, the proteins that regulate RAD51 are the key to understanding how recombination reactions are controlled.Modesti et al., Mol Cell. 2007, this thesis, Chapter 65. Damaged DNA and active replication forks present below a threshold level in the G2 phase might fail to activate checkpoint signaling.Torres-Rosell et al., Science 2007, this thesis, Chapter 56. Restart of the cell cycle following a DNA damage checkpoint arrest is not a default pathway, but requires active signaling.Freire et al., Cell Cycle 20067. It is evident that individuals differ in the ability to repair DNA; however, with the current techniques, it is impossible to measure absolute or relative DNA repair capacity.8. Genomic instability can turn out to be not just the driving force but also the Achil-les’ heel of cancer.Murga and Fernández-Capetillo, Clin Transl Oncol 20079. Translesion synthesis and homologous recombination are likely to be more closely interconnected that generally appreciated.10. Doubt grows with knowledge. Johann Wolfgang von Goethe11. Very little is needed to make a happy life, it is all within yourself, in your way of thinking.Marcus Aurelius26th March 2008Stellingen.indd   1 2/24/08   5:10:43 PM

Cellular Responses to Replication Problems

http://repub.eur.nl/pub/20412/Budzowska-stellingen.pdf

Cellular Responses to Replication Problems

Abstract

Similar works

Full text

Available Versions

EUR Research Repository

EUR Research Repository

Erasmus University Digital Repository