Cellular Damage, Repair & Apoptosis - The Rogers Lab at Yale School of Medicine

Transcript

• 00:05DNA pulls our genomic information,
• 00:07and unfortunately,
• 00:09it's not inert and it's
• 00:10subject to damage.
• 00:13Because we want to be
• 00:14able to preserve our genomic
• 00:16information,
• 00:17cells have evolved this very
• 00:19intricate system called DNA damage
• 00:21response.
• 00:22And there are two main
• 00:23pathways
• 00:24that happen within the system,
• 00:26DNA repair
• 00:28and apoptosis.
• 00:30So if a cell has
• 00:32DNA damage, it can choose
• 00:34to use many different mechanisms
• 00:36to repair that damage.
• 00:38But in cases when there's
• 00:39so much damage, the cell
• 00:41might decide it's in their
• 00:43best interest to activate apoptosis
• 00:45or in other words, its
• 00:47own cell death.
• 00:53My lab is really interested
• 00:54in trying to understand how
• 00:56pathways within the DNA damage
• 00:58response talk to each other.
• 01:01We have a specific interest
• 01:03in altered DNA structures.
• 01:05So DNA, primarily the structure
• 01:08is a duplex, meaning it
• 01:09is comprised of two different
• 01:11strands of DNA.
• 01:12But under some biological
• 01:14processes,
• 01:15cells can actually form altered
• 01:17structures that are different from
• 01:18this duplex.
• 01:20Our lab is focusing on
• 01:21triplex DNA.
• 01:22So that means that instead
• 01:24of having two strands of
• 01:25DNA, the cell then has
• 01:26three strands of DNA.
• 01:28And that three stranded structure
• 01:30is actually recognized by the
• 01:32cell as DNA damage. And
• 01:34we are trying to understand
• 01:36what proteins involved in repair
• 01:38actually are also essential for
• 01:41determining that repair can be
• 01:43efficient.
• 01:44We now need to incorporate
• 01:45and alert
• 01:47apoptosis
• 01:48that it needs to step
• 01:49in in order to preserve
• 01:50genomic integrity.
• 01:57My lab is really using
• 01:59molecular biology and biochemistry
• 02:01techniques to try and understand
• 02:03repair proteins.
• 02:05We use microscopy to look
• 02:07at these proteins on a
• 02:08cellular level and to see
• 02:09where they go within the
• 02:10cell. We also use those
• 02:12microscopy techniques to be able
• 02:14to understand
• 02:15where the DNA damage is,
• 02:17how the damage is getting
• 02:18repaired
• 02:19and we look at this
• 02:20in many different cancer cell
• 02:22lines, in many different cancer
• 02:23types. In particular, my lab
• 02:25is interested
• 02:26in breast cancer and ovarian
• 02:28cancer.
• 02:30In addition to looking at
• 02:31things on a microscopic level,
• 02:33we're also interested in looking
• 02:35at things from a genomic
• 02:36level. So we do bulk
• 02:38RNA sequencing and looking at
• 02:40different genomic techniques so that
• 02:42we can actually see where
• 02:43in the genome across the
• 02:45whole entire cell is this
• 02:46damage happening.
• 02:52There are several different types
• 02:54of cancers, and one type
• 02:56of cancer are cancers that
• 02:57have gene amplification.
• 02:59And so what that means
• 03:00is that the cell has
• 03:02determined that in order for
• 03:03it to grow very aggressively,
• 03:05it will have multiple copies
• 03:07of a gene, and that
• 03:09gene gives it the growth
• 03:10advantage.
• 03:11Traditionally,
• 03:12drug development strategies have been
• 03:14to target those over expressed
• 03:16protein products that happen as
• 03:18a result of the amplified
• 03:20genes. This has been very
• 03:21powerful, but it has been
• 03:23a limiting factor for many
• 03:24other types of cancers where
• 03:26small molecule targeting of those
• 03:28proteins is not effective and
• 03:30it's not
• 03:31doable. And so what my
• 03:32lab has been doing is
• 03:34to find ways to really
• 03:35target these cancers on a
• 03:37genomic level.
• 03:39We can design these synthetic
• 03:41oligonucleotide
• 03:42molecules that bind sequence specifically
• 03:45to the amplified gene. This
• 03:47creates a triplet structure.
• 03:49We know that the triplet
• 03:50structures, if you have enough
• 03:51of them formed, can cause
• 03:53the cell and force the
• 03:54cancer cell to activate its
• 03:56own death.
• 03:57We can use this system
• 03:59of manipulating DNA repair and
• 04:01apoptosis
• 04:02to cause cancer cells to
• 04:03die.
• 04:04I think it has far
• 04:05reaching amplifications
• 04:07because there are over four
• 04:08hundred and fifty genes that
• 04:09are amplified within cancer cells
• 04:11in more than over fourteen
• 04:13subtypes of cancer. So this
• 04:15platform has really broad reaching
• 04:17applications.