Limits...
Taming the tiger by the tail: modulation of DNA damage responses by telomeres.

Lydall D - EMBO J. (2009)

Bottom Line: Telomeres do not, as might be expected, exclude DDR proteins from chromosome ends but instead engage with many DDR proteins.Considerable diversity in telomere structure has evolved in different organisms and, perhaps reflecting this diversity, different DDR proteins seem to have distinct roles in telomere physiology in different organisms.Drawing principally on studies in simple model organisms such as budding yeast, in which many fundamental aspects of the DDR and telomere biology have been established; current views on how telomeres harness aspects of DDR pathways to maintain telomere stability and permit cell-cycle division are discussed.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, HenryWellcome Laboratory, Newcastle University, Tyne and Wear, UK. D.A.Lydall@ncl.ac.uk

ABSTRACT
Telomeres are by definition stable and inert chromosome ends, whereas internal chromosome breaks are potent stimulators of the DNA damage response (DDR). Telomeres do not, as might be expected, exclude DDR proteins from chromosome ends but instead engage with many DDR proteins. However, the most powerful DDRs, those that might induce chromosome fusion or cell-cycle arrest, are inhibited at telomeres. In budding yeast, many DDR proteins that accumulate most rapidly at double strand breaks (DSBs), have important functions in physiological telomere maintenance, whereas DDR proteins that arrive later tend to have less important functions. Considerable diversity in telomere structure has evolved in different organisms and, perhaps reflecting this diversity, different DDR proteins seem to have distinct roles in telomere physiology in different organisms. Drawing principally on studies in simple model organisms such as budding yeast, in which many fundamental aspects of the DDR and telomere biology have been established; current views on how telomeres harness aspects of DDR pathways to maintain telomere stability and permit cell-cycle division are discussed.

Show MeSH

Related in: MedlinePlus

DDR proteins at budding yeast telomeres and DSBs. (A, C, E, G) show the recruitment of DNA damage response proteins to a DSB undergoing HR. (B, D, F, H) show the role of DDR and telomere-capping proteins in forming a capped telomere. (A) A blunt ended DSB. (B) A leading strand telomere after DNA replication. (C) Rapid recruitment of Mre11, Rad50 and Xrs2, Tel1 and Yku70/Yku80 to DSBs. (D) Rapid recruitment of Mre11, Rad50, Xrs2, Tel1 and Yku70/Yku80 to a telomere. (E) Nuclease- and helicase-dependent production of ssDNA generates a substrate for RPA binding. (F) Telomeric (G rich) ssDNA, which is partially Mre11 dependent, provides a substrate for Cdc13, Stn1 and Ten1 binding. (G) RPA-coated ssDNA helps recruite not only HR proteins such as Rad51/Rad52 (not shown) but also checkpoint proteins Rad24, the Rad17, Mec3, Ddc1 heterotrimeric ring. Mec1 and, its partner, Ddc2 bind RPA and help contribute to kinase-dependent signal transduction cascades that can lead to not only cell-cycle arrest, but also a capped telomere (dashed line between G and H). Rad9, essential for signalling cell-cycle arrest at DSBs and cdc13-1 uncapped telomeres, is recruited in part through the interaction with the methylated histone H3 lysine 79. (H) Telomerase is recruited to telomeres, in part, through interactions with Yku80, and with Cdc13.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2722249&req=5

f1: DDR proteins at budding yeast telomeres and DSBs. (A, C, E, G) show the recruitment of DNA damage response proteins to a DSB undergoing HR. (B, D, F, H) show the role of DDR and telomere-capping proteins in forming a capped telomere. (A) A blunt ended DSB. (B) A leading strand telomere after DNA replication. (C) Rapid recruitment of Mre11, Rad50 and Xrs2, Tel1 and Yku70/Yku80 to DSBs. (D) Rapid recruitment of Mre11, Rad50, Xrs2, Tel1 and Yku70/Yku80 to a telomere. (E) Nuclease- and helicase-dependent production of ssDNA generates a substrate for RPA binding. (F) Telomeric (G rich) ssDNA, which is partially Mre11 dependent, provides a substrate for Cdc13, Stn1 and Ten1 binding. (G) RPA-coated ssDNA helps recruite not only HR proteins such as Rad51/Rad52 (not shown) but also checkpoint proteins Rad24, the Rad17, Mec3, Ddc1 heterotrimeric ring. Mec1 and, its partner, Ddc2 bind RPA and help contribute to kinase-dependent signal transduction cascades that can lead to not only cell-cycle arrest, but also a capped telomere (dashed line between G and H). Rad9, essential for signalling cell-cycle arrest at DSBs and cdc13-1 uncapped telomeres, is recruited in part through the interaction with the methylated histone H3 lysine 79. (H) Telomerase is recruited to telomeres, in part, through interactions with Yku80, and with Cdc13.

Mentions: Scores of proteins contribute to cellular responses to DSBs and some of these are listed in Table I. Some proteins engage early with DSBs, others engage later, and with the final repair outcome depending on competition between different repair pathways (Lisby et al, 2004; Symington and Heyer, 2006; Kanaar et al, 2008). The left part of Figure 1 shows some of the budding yeast proteins binding to a DSB as it undergoes HR repair and the right part shows some of the same proteins and telomere-specific proteins playing roles in telomere maintenance. Interestingly, in budding yeast many of the ‘early' DDR proteins at DSBs are involved in physiological telomere maintenance, whereas ‘late' DDR proteins seem, generally, to have less of a role in telomere maintenance. Late DDR proteins do have important functions in the case of telomere failure, either in back up mechanisms of telomere maintenance, such as alternative lengthening of telomeres (ALTs), or inhibiting cell-cycle progression if telomeres are uncapped (Lydall and Weinert, 1995; Enomoto et al, 2002; Lundblad, 2002; IJpma and Greider, 2003).


Taming the tiger by the tail: modulation of DNA damage responses by telomeres.

Lydall D - EMBO J. (2009)

DDR proteins at budding yeast telomeres and DSBs. (A, C, E, G) show the recruitment of DNA damage response proteins to a DSB undergoing HR. (B, D, F, H) show the role of DDR and telomere-capping proteins in forming a capped telomere. (A) A blunt ended DSB. (B) A leading strand telomere after DNA replication. (C) Rapid recruitment of Mre11, Rad50 and Xrs2, Tel1 and Yku70/Yku80 to DSBs. (D) Rapid recruitment of Mre11, Rad50, Xrs2, Tel1 and Yku70/Yku80 to a telomere. (E) Nuclease- and helicase-dependent production of ssDNA generates a substrate for RPA binding. (F) Telomeric (G rich) ssDNA, which is partially Mre11 dependent, provides a substrate for Cdc13, Stn1 and Ten1 binding. (G) RPA-coated ssDNA helps recruite not only HR proteins such as Rad51/Rad52 (not shown) but also checkpoint proteins Rad24, the Rad17, Mec3, Ddc1 heterotrimeric ring. Mec1 and, its partner, Ddc2 bind RPA and help contribute to kinase-dependent signal transduction cascades that can lead to not only cell-cycle arrest, but also a capped telomere (dashed line between G and H). Rad9, essential for signalling cell-cycle arrest at DSBs and cdc13-1 uncapped telomeres, is recruited in part through the interaction with the methylated histone H3 lysine 79. (H) Telomerase is recruited to telomeres, in part, through interactions with Yku80, and with Cdc13.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2722249&req=5

f1: DDR proteins at budding yeast telomeres and DSBs. (A, C, E, G) show the recruitment of DNA damage response proteins to a DSB undergoing HR. (B, D, F, H) show the role of DDR and telomere-capping proteins in forming a capped telomere. (A) A blunt ended DSB. (B) A leading strand telomere after DNA replication. (C) Rapid recruitment of Mre11, Rad50 and Xrs2, Tel1 and Yku70/Yku80 to DSBs. (D) Rapid recruitment of Mre11, Rad50, Xrs2, Tel1 and Yku70/Yku80 to a telomere. (E) Nuclease- and helicase-dependent production of ssDNA generates a substrate for RPA binding. (F) Telomeric (G rich) ssDNA, which is partially Mre11 dependent, provides a substrate for Cdc13, Stn1 and Ten1 binding. (G) RPA-coated ssDNA helps recruite not only HR proteins such as Rad51/Rad52 (not shown) but also checkpoint proteins Rad24, the Rad17, Mec3, Ddc1 heterotrimeric ring. Mec1 and, its partner, Ddc2 bind RPA and help contribute to kinase-dependent signal transduction cascades that can lead to not only cell-cycle arrest, but also a capped telomere (dashed line between G and H). Rad9, essential for signalling cell-cycle arrest at DSBs and cdc13-1 uncapped telomeres, is recruited in part through the interaction with the methylated histone H3 lysine 79. (H) Telomerase is recruited to telomeres, in part, through interactions with Yku80, and with Cdc13.
Mentions: Scores of proteins contribute to cellular responses to DSBs and some of these are listed in Table I. Some proteins engage early with DSBs, others engage later, and with the final repair outcome depending on competition between different repair pathways (Lisby et al, 2004; Symington and Heyer, 2006; Kanaar et al, 2008). The left part of Figure 1 shows some of the budding yeast proteins binding to a DSB as it undergoes HR repair and the right part shows some of the same proteins and telomere-specific proteins playing roles in telomere maintenance. Interestingly, in budding yeast many of the ‘early' DDR proteins at DSBs are involved in physiological telomere maintenance, whereas ‘late' DDR proteins seem, generally, to have less of a role in telomere maintenance. Late DDR proteins do have important functions in the case of telomere failure, either in back up mechanisms of telomere maintenance, such as alternative lengthening of telomeres (ALTs), or inhibiting cell-cycle progression if telomeres are uncapped (Lydall and Weinert, 1995; Enomoto et al, 2002; Lundblad, 2002; IJpma and Greider, 2003).

Bottom Line: Telomeres do not, as might be expected, exclude DDR proteins from chromosome ends but instead engage with many DDR proteins.Considerable diversity in telomere structure has evolved in different organisms and, perhaps reflecting this diversity, different DDR proteins seem to have distinct roles in telomere physiology in different organisms.Drawing principally on studies in simple model organisms such as budding yeast, in which many fundamental aspects of the DDR and telomere biology have been established; current views on how telomeres harness aspects of DDR pathways to maintain telomere stability and permit cell-cycle division are discussed.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, HenryWellcome Laboratory, Newcastle University, Tyne and Wear, UK. D.A.Lydall@ncl.ac.uk

ABSTRACT
Telomeres are by definition stable and inert chromosome ends, whereas internal chromosome breaks are potent stimulators of the DNA damage response (DDR). Telomeres do not, as might be expected, exclude DDR proteins from chromosome ends but instead engage with many DDR proteins. However, the most powerful DDRs, those that might induce chromosome fusion or cell-cycle arrest, are inhibited at telomeres. In budding yeast, many DDR proteins that accumulate most rapidly at double strand breaks (DSBs), have important functions in physiological telomere maintenance, whereas DDR proteins that arrive later tend to have less important functions. Considerable diversity in telomere structure has evolved in different organisms and, perhaps reflecting this diversity, different DDR proteins seem to have distinct roles in telomere physiology in different organisms. Drawing principally on studies in simple model organisms such as budding yeast, in which many fundamental aspects of the DDR and telomere biology have been established; current views on how telomeres harness aspects of DDR pathways to maintain telomere stability and permit cell-cycle division are discussed.

Show MeSH
Related in: MedlinePlus