ATMATM

John BerryJohn Berry

What is ATM?What is ATM? Named “ATM” for “Ataxia-telangiectasia Named “ATM” for “Ataxia-telangiectasia

Mutated” gene. The mutation is Mutated” gene. The mutation is recessive.recessive.

Ataxia-telangiectasia (or AT) is a Ataxia-telangiectasia (or AT) is a neurodegenerative disease that is neurodegenerative disease that is normally detected in infancy to early normally detected in infancy to early childhood. childhood.

AT patients have shown a predisposition AT patients have shown a predisposition to Lymphoma, so ATM was suspected as to Lymphoma, so ATM was suspected as a tumor suppressing gene.a tumor suppressing gene.

http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp

AT SymptomsAT Symptoms

Symptoms: ataxia, telangiectasia, Symptoms: ataxia, telangiectasia, and impairing of the immune systemand impairing of the immune system

http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp

AT SymptomsAT Symptoms

Symptoms: ataxia, telangiectasia, Symptoms: ataxia, telangiectasia, and impairing of the immune systemand impairing of the immune system

http://www.uv.es/derma/CLindex/CLlinfomas/CLmast9.jpghttp://www.uv.es/derma/CLindex/CLlinfomas/CLmast9.jpg

http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp

AT EffectsAT Effects

Patients are subject to Patients are subject to sinopulmonary infections sinopulmonary infections

Increased occurrence of malignant Increased occurrence of malignant tumors.tumors.

Patients have a short life-Patients have a short life-expectancy.expectancy.

http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp

ATMATM

P(3)IK Serine-Threonine KinaseP(3)IK Serine-Threonine Kinase Located in the NucleusLocated in the Nucleus Normally inactivatedNormally inactivated Rapid activation in response to Rapid activation in response to

Double Strand Break (DSB)Double Strand Break (DSB) Substrate list is not presently Substrate list is not presently

complete.complete.

ATM Function ATM Function http://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdfhttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf

ATM SubstratesATM Substrateshttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdfhttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf

ATM Checkpoint FunctionsATM Checkpoint FunctionsShiloh, Yosef. “ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOMEINTEGRITY.” Nature Reviews Cancer. Volume 3 March

2003 pg 155-168

RepairRepairMcKinnon, Peter J. “ATM and Ataxia telangiectasia.”McKinnon, Peter J. “ATM and Ataxia telangiectasia.”EmboEmbo Reports.Reports. Vol 3 (8) 2004. Vol 3 (8) 2004.

pg 772-776pg 772-776

ATM knockout in MiceATM knockout in Mice

ATM -/-: Lymphoma in 2-4 monthsATM -/-: Lymphoma in 2-4 months

Heterozygous mice are predisposed.Heterozygous mice are predisposed.

Loss of Heterozygosity is required in Loss of Heterozygosity is required in mostmost cases cases

Barlow, C, et al. “Atm-deficient mice: a paradigm of ataxia telangiectasia. Barlow, C, et al. “Atm-deficient mice: a paradigm of ataxia telangiectasia. CellCell. .

1996 Jul 12;86(1):159-71.1996 Jul 12;86(1):159-71.

Evidence for the PathwayEvidence for the Pathwayhttp://breast-cancer-research.com/content/pdf/bcr968.pdfhttp://breast-cancer-research.com/content/pdf/bcr968.pdf

ATM +/-, p53 +/- MiceATM +/-, p53 +/- Mice

Irradiated Irradiated double double heterozygoheterozygous mice us mice show the show the highest highest incidence of incidence of carcinogenecarcinogenesissis

http://breast-cancer-http://breast-cancer-research.com/content/pdf/research.com/content/pdf/bcr968.pdfbcr968.pdf

ATM mutations in Human ATM mutations in Human CancerCancer

A-T Patients are not the main health A-T Patients are not the main health concern, but rather carriers of A-T.concern, but rather carriers of A-T.

Most heterozygous individuals do Most heterozygous individuals do not show a pre-disposition to cancernot show a pre-disposition to cancer

Discovery of the dominant negativeDiscovery of the dominant negative

Shiloh, Yosef. “ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOMEINTEGRITY.” Nature Reviews Cancer. Volume 3 March 2003 pg 155-168

ATM Function ATM Function http://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdfhttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf

Future DirectionsFuture Directions

Despite a limited risk group, ATM is Despite a limited risk group, ATM is still important for research.still important for research.

Damage repair is a key component Damage repair is a key component of homeostasis.of homeostasis.

Any Questions?Any Questions?